Antibiotics Definition

A substance produced by one microorganism that selectively kills or inhibits the growth of another.

• Antibiotic: A class of substances that can kill or inhibit the growth of some groups of microorganisms. Originally antibiotics were derived from natural sources (for example penicillin from molds), but many currently used antibiotics are semi-synthetic and modified with additions of manmade chemical components.
• Antimicrobial: In this document, the term “antimicrobial” is used inclusively to refer to any agent (including an antibiotic) used to kill or inhibit the growth of microorganisms (bacteria, viruses, fungi, or parasites). This term applies whether the agent is intended for human, veterinary, or agricultural applications.

History Of Antibiotic Development

• 1928: Alexander Fleming noted that the growth of bacterial colonies is inhibited by the coexistence of fungal colonies. Fleming concluded that the material produced by the fungus is not worth being used clinically because it is difficult to isolate.
• 1930: Florey et al isolated a compound by freeze-drying from the fungus and named it penicillin which has an antibiotic effect.
• 1945: D. Hodgkins illustrated the chemical structure of penicillin and gave the excuse for Fleming’s failure in isolating penicillin (Why?).
• 1957: Sheehan develops a synthetic route for the production of penicillin.
• 1958: Beechams isolates 6-aminopenicillins acid (6-APA) to be used as an intermediate for semi-synthetic penicillin derivatives.
• The careless use of penicillin led to the emergence of bacterial resistance.
• In 1976, Beechams isolated a natural product called clavulanic acid that is effective in preventing enzymatic digestion of penicillin in resistant strains of bacteria.

Read and Learn More Medicinal Chemistry III Notes

Bacterial cell-wall:

• Bacteria have cell walls to survive a large range of environmental conditions, such as varying pH, temperature, and osmotic pressure.
• Human and animal cells have no cell wall, which makes it a perfect target for internally- used antibiotics.
• The structure of the wall consists of a parallel series of sugar backbones containing two types of sugar [ N -acetylmuramic acid (NAM) and N – acetyl glucosamine (NAG)].

Batalactum Antibiotics

The p-lactam antibiotics are a large class of diverse compounds used clinically in both the oral and parenteral forms. The p-lactam antibiotic agents have become the most widely used therapeutic class of antimicrobials because of their broad antibacterial spectrum and excellent safety profile.

Biosynthesis of penicillin: It is synthesized within the penicillium by fusing two amino acids (L-cysteine and L- valine)The acyl side chain (R) varies, depending on the components of the fermentation medium.

Synthesis Of Penicillin Analogues

1. Fermentation: Addition of different carboxylic acids to fermentation medium to produce penicillin with different acyl side chains – Only suitable for unbranched carboxylic acids – Tedious and time-consuming.
2. Complete synthesis: Long processes and low-yielding (1%)
3. Semi-synthesis: Use a carboxylic acid-deficient fermentation medium to generate 6-aminopenicillanic acid. – 6- APA is (a very weak antibiotic) and reacts with different acyl chlorides to synthesize penicillin analogs.

Penicillin: All penicillins are derivatives of 6-aminopenicillin acid (thiazolidine ring is attached to a p—p-lactam ring that carries a secondary amino group (RNH—)) and contains a beta-lactam ring structure that is essential for antibacterial activity.

• Beta-lactam antibiotics are narrow-spectrum and bactericidal drugs. Penicillin is obtained from P. cryssogenum.
• Penicillin is degraded by the acidic pH and amide linkage destruction through the b-lactamase enzyme which is produced by gram-negative bacteria. Beta-lactams act only by multiplying cells.

Mechanism Of Action Of Penicillin

They act as an irreversible inhibitor of the enzyme transpeptidase, an enzyme bacteria use to make their cell walls.

• The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidase known as penicillin-binding proteins (PBPs).
• PBPs bind to the D-Ala-D-Ala at the end of muropeptides, the peptidoglycan precursors to crosslink the peptidoglycan.
• p-lactam antibiotics mimic the site and competitively inhibit PBP cross-linking of peptidoglycan.

Penicillin Classification

1. Naturalpenicillin’s:

• Benzylpenicillin (penicillin G)
• Phenoxy methyl penicillin (penicillin V)

Effective Against: Gram-positive + Less effective against Gram-negative bacteria.

Treatment For Naturalpenicillin’s:

• Tonsillitis.
• Anthrax.
• Rheumatic fever.
• Streptococcal skin infections

Characteristics of Natural Penicillin:

• Narrow spectrum.
• Should be given orally.
• Prone to beta-lactamase.

Problems with Penicillin G:

• It is sensitive to stomach acids.
• It is sensitive to (i-lactamases – enzymes which hydrolyze the [Mactam ring.
• It has a limited range of activities.

2. Aminopcnicillin’s

• Ampicillin.
• Amoxicillin.

The group has the following properties:

1. Hydrophilic NH₂ group attached to C that is u to C=0 of the acyl side chain
2. The acid stability is enhanced due to the electron-withdrawing effect of Nl L
3. No bulky groups at acyl side chain 4 more sensitive to [Mactanuso.
4. And COOH groups are ionized with poor absorption from the gut.
5. The ionizable groups can be masked to form prodrugs with better absorption
6. The ci-carbon becomes chiral (activity of D-isomer  L-isomer and penicillin G)

–

 

Ampicillin and amoxicillin have:

1. It has a similar spectrum to Penicillin G but is more active against Gram-ve cocci and enterobacteria.
2. Inactive against P. aeruginosa.
3. Non-toxic and can be taken orally.
4. High doses change gut flora problems such as diarrhea.

3. Broad spectrum penicillin’s

Ureidopenicillins:

• Piperacillin
• Mezocillin
• Azlocillin

The group has the following properties:

1. Urea functional group attached to C that is a to C=0 of the acyl side chain.
2. More active vs. Gram-ve than carbenicillin (more cell-mem permeability).
3. Higher activity against P. aeruginosa.
4. p-lactamase sensitive.
5. Acid-sensitive.

Stereochemistry And Iupac Of Beta – Lactum Ring

• It has a total of three chiral carbons 3,5 and 6.
• All synthetic and semi-synthetic penicillin have the same absolute configuration (like 3S 5R, 6R).
• Acyl amino and carboxylic acid Trans to each other.
• The lead molecule in the discovery of semi-synthetic penicillin is 6 amino penicillinic acid (6-APA).
• 6-APA is structurally derived from L-valine and L-cysteine.
• All penicillins have a Penam ring as a basic moiety.
• Certain strands of microorganisms destroy p-Lactam antibiotics enzymatically like Penicillanase or p-Lactamase (Open the p-Lactam ring).

Structure-Activity Relationship Of Penicillin:

• Amide and carboxylic acid are involved in binding.
• Carboxylic acid binds as the carboxylate ion.
• The mechanism of action involves the p-lactam ring.
• Activity related to p-lactam ring strain (subject to stability factors).
• The bicyclic system increases the p-lactam ring strain.
• Not much variation in structure is possible.
• Variations are limited to the side chain (R).

β-Lactamase Inhibitors

Clavulanic acid:

• Weak, unimportant antibacterial activity
• Powerful irreversible inhibitor of (β-lactamases) – suicide substrate
• Used as a sentry drug for ampicillin
• Augmentin = ampicillin + clavulanic acid [drug of choice for GIT infection]
• Allows less ampicillin per dose and an increased activity spectrum
• Timentin = ticarcillin + clavulanic acid Penicillanic acid sulfone derivatives

Penicillanic acid Sulfone Derivatives

Sulbactam

Tazobactam:

• Suicide substrates for (β-lactamase enzymes
• Sulbactam has a broader spectrum of activity as (β-lactamases) than clavulanic acid but is less potent
• Unasyn = ampicillin + sulbactam
• Tazobactam has a broader spectrum of activity as (β-lactamases) than clavulanic acid and has a similar potency
• Tazocin or Zosyn = piperacillin + tazobactam

Some Important Knowledge About Penicillins:

1. Penicillin, abbreviated as PCN or pen, is a group of antibiotics that resulted from Penicillium fungi. It is used in the treatment and prevention of diseases caused by Gram-positive organisms, such as syphilis and infections caused by staphylococci and streptococci.
2. Several penicillin types counter bacteria to a variety of extents.
3. Some of these are flucloxacillin, ampicillin, phenoxymethyl penicillin, and amoxicillin.
4. These fungi were originally discovered by a medical student, Ernest Duchesne, in the late 19th Century, and then re-discovered by Alexander Fleming, in 1928, for their antibiotic properties.
5. He realized this when a sample of a certain bacteria that he was studying, Staphylococcus, got infected by some mold, and all bacteria cells closest to the mold were perishing.
6. With further testing, Fleming learned the mold was creating a bacteria-demolishing substance, which he named penicillin. ,
7. The disease-causing bacteria constantly rebuild their cell walls to protect themselves and maintain their structure. Penicillins work by penetrating and destroying these cell walls, consequently killing the bacteria cells.

Cephalosporins

Cephalosporins comprise a large group of semi-synthetic drugs, most of which are derived from cephalosporin C, a substance obtained from a species of Cephalosporium.

 

Cephalosporins have a p-lactam ring and a dihydrothiazine ring (7-aminocephalosporanic acid). Additions of any side chain in the p-lactam ring at 7 positions modify the spectrum of activity and the dihydrothiazine ring at 3 positions modify the pharmacokinetic properties.

• Ring A is a four-member p-Lactam ring and Ring B is a six-membered Dihydrothizine ring.
• Cephalosporin having cepham as a basic moiety
• Like 6-APA in penicillin, 7-Amino cephalosporin acid is a lead molecule for the synthesis of semi-synthetic cephalosporin
• Cephalosporin C-True cephalosporin or 7-ACA  Cephalosporin P-Acidic antibiotics or Steroidal antibiotic (Fusidin)
• Fusidin- It is a sodium salt of fusidic acid.
• Cephalosporin N-Derivative of 6-APA, Also known as Synnematin N nowadays, is known as Penicillin N.
• All cephalosporins are bactericidal and have the same mechanism of action as penicillin cell wall synthesis inhibition.
• Cephalosporins have greater acid and p-lactamase resistance properties and a wide range of antibacterial activity.
• Most cephalosporins are excreted primarily by renal tubular secretions probenecid inhibits tubular secretion like penicillins.

Cephalosporin Classification

Structure-Activity Relationship Of Cephalosporins

1. Beta-Lactam Ring:

• Required for PBP reactivity and antibacterial activity
• Reactivity is reduced compared to the penicillins (2 reasons)
• Compare mechanism of action, resistance, pharmacodynamics, etc to penicillins

2. 2-Carboxyl Group:

• Acidic: Salt formation, product formulation Prodrug formation Elimination
• profile: Renal

3. X-Substituent:

• Cephalosporins and cephamycins
• Determines, in part, resistance to beta-lactamase inactivation

4. 3- Substituent (R3):

• Chemical or acid stability or instability or Metabolic stability or instability
• Minimal impact on antibacterial activity
• Protein binding and half-life: Heterocycles
• Adverse Reaction and Drug Interaction

5. 7- Substituent (R7):

• Incorporated by semi-synthesis:
• Impact on the spectrum of activity (beta-lactamases, PBP affinity, etc.)
• Significant role in activity and classification by generation

Adverse Reaction

• Pain at the site of (i.m.) injection.
• Diarrhea and hypersensitivity reactions like penicillins.
• Nephrotoxicity is highest with cephaloridine.
• Platelet dysfunction and bleeding Disulfiram-like reaction.

Uses

• In penicillin-producing staphylococcal infections Example cephalothin.
• Gonorrhea is caused by penicillinase-producing organisms; for Example cefuroxime and cefotaxime.
• Septicemias are caused by gram-negative organisms.

Other β- Lactam Antibiotics

Monobactams: Aztreonam is a monocyclic novel p-lactam antibiotic that has resistance to β-lactamase. It is active against gram-negative bacilli, H. influenza, and Pseudomonas but does not affect gram-positive cocci.

• It is used in patients allergic to penicillin or cephalosporins.
• Adverse effect: hypersensitivity reactions and thrombophlebitis.

Carbapenems

Imipenem:

Ertapenem:

• Penicillin-like, but the sulfur atom of the thiazolidine ring is replaced with a carbon atom.
• These are potent and very broad-spectrum, β-lactam antibiotics. It is resistant to (β- lactamase).
• Unlike Meropenem and Ertapenem, Imipenem is rapidly inactivated by dehydroxypeptidase.
• For this reason, imipenem combined with a dehydroxypeptidase inhibitor called cilastatin, which has similar pharmacokinetics to imipenem
• Probencid inhibits tubular secretion of imipenem-like penicillins.
• Carbapenem exerts cross-sensitivity with penicillins.
• Cephalosporins and other beta-lactams should not be administered to patients who are allergic to these drugs.
• Contraindicated in epileptic patients, higher dosage can produce convulsions.

Antibiotics Multiple Choice Questions

Question 1. Cephalosporin is obtained by

1. P. notatum
2. P.acrcmonium
3. S. Venezuela
4. None

Answer:2. P.acrcmonium

Question 2. Cephalosporin is contained.

1. Thiazolidine
2. Dihydrothiazine
3. Purines
4. Pyrimidines

Answer:2. Dihydrothiazine

Question 3. The starting material of Cephalosporin…

1. 6-amino penicillinic acid
2. 6-amino cephalosporin acid
3. Phenylalanine
4. All

Answer:2. 6-amino cephalosporin acid

Question 4. Cephalosporin excreted by

1. Renal tubular secretion
2. Sweat secretion
3. Both
4. None

Answer:1. Renal tubular secretion

Question 5. Which one is first-generation cephalosporin?

1. Cefalexin
2. Cefoperazone
3. Cefepime
4. None

Answer: 1. Cefalexin

Question 6. The antimicrobial action of penicillin is the inhibition of

1. Protein synthesis
2. Cell wall synthesis
3. Cell membrane synthesis
4. DNA synthesis

Answer:3. Cell membrane synthesis

Question 7. The beta-lactam antibiotics are

1. Penicillin
2. Cephalosporin
3. Imipenem
4. All of the above

Answer: 4. All of the above

Question 8. The antimicrobial activity of penicillin is due to

1. Thiazolidine ring
2. Beta-lactam ring
3. 6-APA
4. None

Answer: 2. Beta-lactam ring

Question 9. Which of the following is an anti-seudomonal penicillin?

1. Carbenicillin
2. Methicillin
3. Ampicillin
4. Azlocillin

Answer: 2. Methicillin

Question 10. How much chiral carbon is present in the penicillin structure?

1. 1
2. 2
3. 3
4. 4

Answer:3. 3

Question 11. Which enzyme is responsible for the formation of the cell wall of bacteria?

1. Amylase
2. Transpetidase
3. Mono oxidase
4. None

Answer: 2. Transpeptidase

Antibiotics Short Answer Questions

Question 1. Which enzyme is responsible for breaking the beta-lactam ring?
Answer: Beta-lactamase enzyme one is responsible for the breakdown of the penicillin ring.

Question 2. Which ring is present in penicillin?
Answer:

All penicillins are derivatives of 6-aminopenicillins added (thiazolidine ring is attached) to a (β- β-lactam ring that carries a secondary amino group (RNH-)) and contains a beta-lactam ring structure that is essential for antibacterial activity.

Question 3. Write various types of components present in bacterial cell walls.
Answer:

Various types of components present in bacterial cell walls: The bacterial cell wall is mainly composed of peptidoglycan which is a mucopolysaccharide that mainly contains N- N-acetyl glucosamine and N-acetyl muramic add.

Question 4. Write the mechanism of action of penicillin.
Answer:

The mechanism of action of penicillin: They act as an irreversible inhibitor of the enzyme transpeptidase, an enzyme bacteria use to make their cell walls. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidase known as penicillin-binding proteins (PBPs). PBPs bind to the D- Ala-D-Ala at the end of muropeptides, the peptidoglycan precursors to crosslink the peptidoglycan. p-lactam antibiotics mimic the site and competitively inhibit PBP cross-linking of peptidoglycan.

Question 5. Which enzyme is responsible for the cross-linking of NAG and NAM?
Answer:

Enzyme transpeptidase is an enzyme bacteria use to make their cell walls. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidase known as penicillin-binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of mucopeptides, the peptidoglycan precursors to crosslink the peptidoglycan.

Question 6. Write the mechanism of action of cephalosporin.
Answer:

Mechanism of action of cephalosporin: They act as an irreversible inhibitor of the enzyme transpeptidase, an enzyme bacteria use to make their cell walls. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidase known as penicillin-binding proteins (PBPs).

Question 7. Write the specific feature of aztreonam.
Answer:

The specific feature of aztreonam: It is a monocyclic novel (β-lactam antibiotic that has resistance to (β-lactamase). It is active against gram-negative bacilli, H. influenza, and Pseudomonas but does not affect gram-positive cocci.

Question 8. Write the example of a third-generation cephalosporin.
Answer:

An example of a third-generation cephalosporin: Ceftriaxone, Cefoperazone, Cefotaxime

Question 9 . Write the example of carbapenems.
Answer:

Example of carbapenems: Imipenem, Meropenem, Ertapenem

Question 10. Write the uses of Cephalosporins.

Answer:

Uses of Cephalosporins

• In penicillin-producing staphylococcal infections Example, cephalothin.
• Gonorrhea is caused by penicillinase-producing organisms; for Example cefuroxime and cefotaxime.
• Septicemias are caused by gram-negative organisms.

Anti Malarial Agents Introduction

Malaria in humans is caused by infection with protozoa parasites of the genus Plasmodium.

1. These parasites spend an asexual phase in men and a sexual phase in female anopheles mosquitoes.
2. Out of several hundred known anopheles species, the four species, which infect man are:

• Plasmodium Falciparum
• Plasmodium Vivax
• Plasmodium malariae
• Plasmodium ovale

Etiology Of Malaria

Malaria is a life-threatening disease. It’s typically transmitted through the bite of an infected Anopheles mosquito.

• Infected mosquitoes carry the Plasmodium parasite. When this mosquito bites you, the parasite is released into your bloodstream.
• Once the parasites are inside your body, they travel to the liver, where they mature. After several days, the mature parasites enter the bloodstream and begin to infect red blood cells.

• Within 48 to 72 hours, the parasites inside the red blood cells multiply, causing the infected cells to burst open.
• The parasites continue to infect red blood cells, resulting in symptoms that occur in cycles that last two to three days at a time.
• Malaria is typically found in tropical and subtropical climates where the parasites can live. The World Health Organization (WHO) states that, in 2018, there were an estimated 216 million cases of malaria in 91 countries.

Read and Learn More Medicinal Chemistry III Notes

What Causes Malaria

Malaria can occur if a mosquito infected with the Plasmodium parasite bites you. Four kinds of malaria parasites can infect humans: Plasmodium vivax, P. ovale, P. malariae, and P. falciparum.

• P. falciparum causes a more severe form of the disease and those who contract this form of malaria have a higher risk of death. An infected mother can also pass the disease to her baby at birth. This is known as congenital malaria.
• Malaria is transmitted by blood, so it can also be transmitted through:
• an organ transplant
• a transfusion
• use of shared needles or syringes

What Are The Symptoms Of Malaria

The symptoms of malaria typically develop within 10 days to 4 weeks following the infection. In some cases, symptoms may not develop for several months. Some malarial parasites can enter the body but will be dormant for long periods Common symptoms of malaria include:

• shaking chills that can range from moderate to severe
• high fever
• profuse sweating
• vomiting
• abdominal pain.
• diarrhea
• anemia
• muscle pain
• convulsions
• coma
• bloody stools

How Is Malaria Diagnosed

Your doctor will be able to diagnose malaria. During your appointment, your doctor will review your health history, including any recent travel to tropical climates. A physical exam will also be performed.

• Your doctor will be able to determine if you have an enlarged spleen or liver. If you have symptoms of malaria, your doctor may order additional blood tests to confirm your diagnosis.
• These tests will show:
• whether you have malaria
• what type of malaria do you have
• if your infection is caused by a parasite that’s resistant to certain types of drugs
• if the disease has caused anemia
• if the disease has affected your vital organs

Tips To Prevent Malaria

There’s no vaccine available to prevent malaria. Talk to your doctor if you’re traveling to an area where malaria is common or if you live in such an area. You may be prescribed medications to prevent the disease.

• These medications are the same as those used to treat the disease and should be taken before, during, and after your trip.
• Talk to your doctor about long-term prevention if you live in an area where malaria is common. Sleeping under a mosquito net may help prevent being bitten by an infected mosquito. Covering your skin or using bug sprays may also help prevent infection.
• If you’re unsure if malaria is prevalent in your area, the CDC has an up-to-date map of where malaria can be found.

How Is Malaria Treated

Malaria can be a life-threatening condition, especially if you’re infected with the parasite P. falciparum. Treatment for the disease is typically provided in a hospital. Your doctor will prescribe medications based on the type of parasite that you have.

• In some instances, the medication prescribed may not clear the infection because of parasite resistance to drugs. If this occurs, your doctor may need to use more than one medication or change medications altogether to treat your condition.
• Additionally, certain types of malaria parasites, such as P. vivax and P. ovale, have liver stages where the parasite can live in your body for an extended period and reactivate at a later date causing a relapse of the infection.
• If you’re found to have one of these types of malaria parasites, you’ll be given a second medication to prevent a relapse in the future

Malaria Classification

Quinoline Derivative Cinchona alkaloids

• Quinine
• Quinidine,
• Cinchonine
• Cinchodine

• All four derivatives of 4-quinoline methanol are linked with a substituted quinclidine moiety.
• Quinine (1-isomer) has anti-malarial activity while d-isomer Quinidine has anti arrythmatic agent.

Quinine-

• Most active ingredients (5%) of cinchona bark
• It has schizonticidal and gametocidal for Plasmodium vivex species.
• SC and IM injection form is not used due to local tissue damage.
• Many times, it is administered with pyrimethamine, sulfadoxine, doxycycline, or mefloquine.
• It is affected against erythrocytic Merozoites.
• It is used in chloroquine resistance plasmodium falciparum infection.
• A high dose of quinine may cause quinidine, like a depressant effect on the heart vasodilation and hypotension.

Quinine Adverse Effects:

Cinchonism, Nocturnal leg cramps: A high dose of quinine may produce a quinidine-like depressant effect on the heart causing vasodilation and may produce hypotension

SAR:

• 2° Alcohol in the structure of quinine alkaloids is responsible for the activity, and Ri (-OCH₂) and R₂ (-CH=CH₂) groups are not responsible for the activity.
• Quinine antagonizes the action of physostigmine on skeletal muscle by exerting a Curare-like effect.
• Due to its low therapeutic index, it is not used alone and is always used in combination (Primaquine, Pyrimethamine, and Sulphonamide0

4-Amino quinoline derivatives:

Example, Chloroquine, Hydroxychloroquine, Amodiaquine

Mechanism of action:

• It is concerted in parasitized red cells where it binds to double-strand DNA.
• This results in inhibition of DNA and RNA polymerase function.
• It is used for the treatment of all types of malaria except “Chloroquine resistance Plasmodium falciparum”.

SAR: In chloroquine 7-chloro, 30 Amine and aminoalkyl side chains are required for activity

Metabolite: Desethyl chloroquine, Bidesethyl chloroquine Adverse effect

• Bone marrow depression, Ratinopathy
• Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency
• Photo allergic dermatitis since it accumulates into the skin Amodiaquin

Metabolite Mechanism of action: Ferriprotoporphyrin, which is released by plasmodium containing erythrocytes acting as chloroquin receptor.

• The combination of Ferriprotoporphyrin and chloroquin causes lysis of parasites and or erythrocyte membranes.
• The quinone imine system is similar to the acetaminophen toxic metabolite.
• Hydroxychloroquine group on ethyl group of diethyl amino group.

8-Amino quinoline: For example, Primaquin, Pamaquin, and Quinocide have asymmetric centers in their structure but Pentaquin does not have them.

Amino quinoline Adverse effect:

• Hemolytic anemia
• Leucopenia
• Methemoglobinemia

Metabolite 5-Hydroxy primaquine and 5-Hydroxy 6-desmethyl primaquine

Metabolite  Mechanism of action:

• Interferes in protein synthesis with enzymes and with erythrocyte phospholipids metabolism in parasites.
• Primaquine inhibits the gametocyte stage; the levo isomer is less active than the dextro isomer.

9-Aminoacridines derivatives: Quinacrine, Acriquin, Aminoacrichin

• They all have acridine rings in their structure.
• Yellow pigmentation of the skin and yellow color appear in the urine along with acridine dye.

Aminoacridines derivatives Adverse effect- Aplastic anemia

Aminoacridines derivatives Mechanism of action:

• It acts at many sites within the cells including the intercalation of DNA strands
• It is tumorigenic and mutagenic and used as a sclerosing agent.

2,4-Diaminnopyrimidine Derivative:

• Pyrimethamine, Trimethoprim
• Used in the exoerythrocytic and erythrocytic phase of disease

Diaminnopyrimidine Derivative Mechanism of Action: It causes selective inhibition of the protozoal enzyme DHFR (Dihydro folate reductase) to disturb the protozoal DNA synthesis and finally death of Protozoal cells.

SAR points:

• Electron donating group at C-6 position
• Cl at Para position
• Two rings are not separated by carbon atoms.

Pyrimethamine: Used in chloroquine resistant falciparum malaria

Biguanides:

• It is a prodrug and is not active until it is not metabolized in vivo to dihydro triazine.
• Prongunil (Chloroguanil) is metabolized to an active triazine ring having anti-malarial activity.

Atovaquone: It is a naphthoquinone derivative used in combination with proguanil administered in the ratio (2.5:1)

Mechanism of action: It interferes with deoxy thymidylate synthesis by inhibiting the dihydrofolate reductase enzyme.

Sulphone and sulphonamide: Long-acting sulphonamide is used in combination with Pyrimethamine/Trimethoprim. E.g., Dapson

Miscellaneous Mefloquine:

• Antibiotics: Doxycycline, Clindamycin, lincomycin, Chloramphenicol ^ Halofantrine: It is a phenanthrene derivative
• Artemisinin: It is a natural product excreted from the dry leaves of Artemisia anna.
• The key structure is to be a “Trioxane” ring consisting of endoperoxide and doxepine oxygen.
• Artemisinin is reduced to dihydroartemisinin, having asymmetric carbon forms.

• Artemether and artemotil are oil-soluble or non-polar methyl or ethyl salts of artemisinin.
• Artesunate is a water-soluble or polar hemisuccinate salt of Artemisinin.

Synthesis Of Chloroquine

Synthesis Of pamaquine

Anti Malarial Agents Multiple Choices Question And Answers

Question 1. Atovaquoneis…

1. Napthaquinone Derivative
2. Trioxane Derivative
3. Guanidine derivative
4. None

Answer: 1. Napthaquinone Derivative

Question 2. Pamaquine containing

1. Quinoline ring
2. Isoquinoline
3. Indole ring
4. All

Answer: 1. Quinoline ring

Question 3. Halofantrine Contains

1. Phenanthracene ring
2. Anthracene ring
3. Naphthalene ring
4. Benzene ring

Answer: 1. Phenanthracene ring

Question 4. Quinine obtained from

1. Cinchona bark
2. cinchona leaf
3. Both
4. None

Answer: 1. Cinchona bark

Question 5. Adverse effect Of

1. Hemolytic anemia
2. sickle cell anemia
3. Aplastic Anemia
4. None

Answer: 1. Hemolytic anemia

Anti Malarial Agents Short Question And Answers

Question .1 Write the mode of action of quinine.
Answer:

Mode of action of quinine: It has Schizonticidal and gametocidal for Plasmodium vivex species.

Question .2 Write the mode of action of biguanide.
Answer:

The mode of action of biguanide: It interferes with deoxy thymidylate synthesis by inhibiting the dihydrofolate reductase enzyme.

Question .3 Write the adverse effect of primaquine.
Answer:

The adverse effect of primaquine: Hemolytic anemia Leucopenia Methemoglobinemia.

Question .4 Write the adverse effect of chloroquine.
Answer:

Adverse effects of chloroquine: Bone marrow depression, Retinopathy Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency Photo allergic dermatitis since it accumulates into the skin Amodiaquin

Question .5 Write the mode of action of pyrimethamine.
Answer:

Mode of action of pyrimethamine: It causes selective inhibition of the protozoal enzyme DHFR (Dihydro folate reductase) to disturb the protozoal DNA synthesis and finally death of protozoal cells.

Question .6 Write the mode of action of amodiaquine.
Answer:

Mode of action of amodiaquine: It is concerted in parasitized red cells where it binds to double-strand DNA. This results in inhibition of DNA and RNA polymerase function.

Anti Tubercular Agents Introduction

Tuberculosis

It is a disease of respiratory transmission. A person gets infected when he comes in contact with an environment contaminated with viable tubercle bacilli. It spreads through coughing, sneezing, and shouting of an infected person.

Causative Organism: Mycobacterium Tuberculosis

Isoniazid

It is a hydrazide of iso-nicotinic acid.

• The structure of INH is similar to Pyridoxine (Vit B₆).
• Bacteriostatic in action

Mechanisam Action: INH inhibits Mycolase Synthase, an enzyme necessary for the biosynthesis of mycolic acid (essential constitute of the mycobacterial cell wall).

Metabolism: N-acetylation, depends upon the transfer of the acetyl group from coenzyme A by N-acetyl transferase.

• The rate of acetylation is genetically controlled.
• Acetyl hydrazine: Toxic metabolite of INH which is responsible for hepatotoxicity.

Metabolism Adverse Effect:

• Peripheral Neuritis-Co administration of Pyridoxine (Vit B6) with INH prevents the symptoms of peripheral neuritis.
• GIT disturbance (Constipation, Loss of appetite)
• Hepatotoxicity

Read and Learn More Medicinal Chemistry III Notes

Metabolism Drug Interaction:

• Antacid (Aluminum Hydroxide) Inhibits the absorption of INH.
• PAS-Inhibits metabolism.
• INH also inhibits the metabolism of Phenytoin and carbamazepine.

streptomycin

Aminoglycoside antibiotic

• Bacteriostatic in action
• Used always in combination
• Nephrotoxicity and ototoxicity are major side effects.
• Streptomycin resistance strain treated with kanamycin and viomycin.

Ethambutol Or Myambutol

• The activity of EMB is stereospecific, dextro isomer having maximum activity than the levo form.
• It has two chiral centers.

Mechanism of action:

It inhibits the “Arabinosyl transferase enzyme” to prevent the polymerization of arabinoglycan in the mycobacterial cell wall.

• Ethambutol if used in a dose of 25 mg/kg per day for more than 9 months can cause Reterobulbar Neuritisimpairment of visual activity and red-green color discrimination.
• Ethambutol decreases renal excretion and it may produce gouty arthritis.
• Contraindicated in pregnancy and children below 2 years.
• A monthly eye examination of the patient is necessary when the patient is treated with EMB.

Rifampicin

It is an orally active bactericidal semi-synthetic derivative of rifamycin B.

• It is obtained from Streptomyces mediterranei.
• It is also known as Ansamycin antibiotics.

Rifampicin Mechanism of action: It strongly binds to the p subunit of bacterial ‘DNA dependent RNA polymerase’ enzyme. Thereby inhibits the RNA synthesis of bacteria. Mammalian RNA polymerase does not bind to rifampicin.

Rifampicin Adverse effect:

• Hepatitis risk may increase when used in combination with INH.
• The flu-like syndrome is characterized by fever, chills, myalgias, and thrombocytopenia.
• Rifampicin imparts a harmless red-orange color to urine.

Rifampicin Drug Interaction: Rifampicin has enzyme induction properties and hence accelerates the metabolism of several drugs like oral contraceptives, anti-coagulants, and protease enzymes.

Pyrazinamide

• It is a pyrazine analog of nicotinamide (containing a pyrazine ring).
• Principle metabolites are Pyrazinoic acid (Active metabolite) and 5-Hydroxy pyrazinoic acid.

Pyrazinamide : (PZA) Mechanism of Action: PZA enters the cell wall of M. tuberculosis via passive diffusion and it is converted to pyrazinoic acid (Active metabolite) by pyrazinamidase enzyme. Then later it inhibits mycobacterial fatty acid synthase-I enzyme and disrupts mycolic acid synthesis needed for mycobacterium cell wall synthesis.

Second Line Agent

Ethionamide:

R = -C₂H₅ = Ethionamide 2 – ethyl thiosonicotinamide

R = -C₃H₇ = Prothionamide-2-propyl thiosonicotinamide

• Prothionamide Or Ethionamide are congeners of this nicotinamide.
• It is also known as the Thioamide analog of Isoniazide.

Ethionamide Mechanism of Action: It may interfere with peptide synthesis by acting as an antimetabolite and inhibiting the incorporation of sulfur (-SH) containing amino acids. (Cysteine, methionine)

P-Amiito Salicylic acid:

• Because of its sour taste and irritant nature, this drug is mainly used in the form of its Na+, K+, and Ca+ salts.

Mechanism of action: Same as sulphonamide

sulphonamide Adverse effect

• Crystalluria
• Lupas like syndrome
• GIT irritation

Thiacetazone:

Chemically, it is a thiosemicarbazone derivative.

Cycloserine:

• Analog of D alanine
• Chemically, D-4-amino 3-isoxazolidone.
• Broad spectrum antibiotics.
• Steriochemically similar to D-Serine.

Cycloserine Adverse Effect

• Peripheral Neuritis
• Tremors
• Psveotlc
• Behavioral changes

Synthesis Of Isoniazid

Synthesis Of Para Amino Salicylic Acid

Anti Tubercular Agents Multiple Choice Question And Answers

Question 1. Isoniazid is

1. Pyridine derivative
2. Trioxane derivative
3. Guanidine derivative
4. None

Answer: 1. Pyridine derivative

Question 2. Isoniazid act on

1. Mycolic acid
2. Arabinose galactose
3. Cox
4. All

Answer: 1. Mycolic acid

Question 3. Ethambutol act on

1. Mycolic acid
2. Arabino galactose
3. Cox
4. All

Answer: 2. Arabino galactose

Question 4. Neurotoxicity is the adverse effect of

1. Isoniazid
2. Ethambutol
3. Both
4. None

Answer: 1. Isoniazid

Question 5. Visualdisruotion Adverse Effect of

1. Isoniazid
2. Pyrazinamide
3. Ethambutol
4. None

Answer: 3. Ethambutol

Anti Tubercular Agents Short  Question And Answers

Question. 1 Write the mode of action of isoniazid.
Answer:

Mode of action of isoniazid: INH inhibits Mycolase Synthase, an enzyme necessary for the biosynthesis of mycolic acid (essential constitute of mycobacterial cell wall).

Question .2 Write the mode of action of pyrazinamide.
Answer:

Mode of action of pyrazinamide

PZA enters me cell wall of M. tuberculosis via passive diffusion and it is converted to pyrazine acid (Active metabolite) by the pyrazinamide enzyme. Then later it inhibits mycobacterial fatty acid synthase-I enzyme and disrupts mycolic acid synthesis needed for mycobacterium cell wall synthesis.

Question. 3 Write the adverse effect of Cycloserine.
Answer:

The adverse effect of Cycloserine

• Peripheral Neuritis
• Tremors
• Psychotic
• Behavioral changes

Question .4 Write the adverse effect of isoniazid.
Answer:

The adverse effect of isoniazid: Peripheral Neuritis-Co administration of Pyridoxine (Vit B6) with INH prevents the symptoms of peripheral neuritis. GIT disturbance (Constipation, Loss of appetite) Hepatotoxicity

Question .5 Write the mode of action of Rifampicin.
Answer:

The mode of action of Rifampicin: It strongly binds to the [3 subunit of bacterial ‘DNA dependent RNA polymerase’ enzyme. Thereby inhibits the RNA synthesis of bacteria. Mammalian RNA polymerase does not bind to rifampicin.

Question 6. Write the adverse of Rlfamplcin.
Answer:

The adverse of Rlfamplcin: Hepatitis risk may increase when used in combination with INH. A flu-like syndrome is characterized by fever, chills, myalgias, and thrombocytopenia. Rifampicin imparts a harmless red-orange color to urine.

Urinary Tract Anti Infective Agents Introduction

Urinary tract infection (UTI) is defined as significant bacteriuria in the presence of a constellation of symptoms such as dysuria (painful urination), increased urinary frequency and urgency, suprapubic discomfort, and costovertebral angle tenderness.

• It is a common cause of infections, particularly among young, sexually active women; an estimated 1 in 3 women will develop a urinary tract infection before the age of 24 years.
• Infection may involve either only the lower urinary tract or both the upper and lower tracts.
• The term cystitis is used to describe the syndrome involving dysuria, and suprapubic tenderness with urinary frequency and urgency.
• These symptoms may also be related to lower tract inflammation without bacterial infection and can be caused by urethritis (for example gonorrheal or chlamydial urethritis).
• Acute pyelonephritis refers to the syndrome of cystitis accompanied by significant bacteriuria and acute infection in the kidney it is characterized by clinical symptoms such as flank pain, fever, dysuria, urinary urgency, and frequency.

Classification Of Drugs

Fluoroquinolones:

• The fluoroquinolones are a family of synthetic, broad-spectrum antibacterial agents with bactericidal activity. The parent of the group is nalidixic acid, discovered in 1962 by Lescher and colleagues.
• The first fluoroquinolones were widely used because they were the only orally administered agents available for treating serious infections caused by gram-negative organisms, including Pseudomonas species.
• The newer fluoroquinolones have a wider clinical use and a broader spectrum of antibacterial activity including gram-positive and gram-negative aerobic and anaerobic organisms.
• Some of the newer fluoroquinolones have an important role in the treatment of community-acquired pneumonia and intra-abdominal infections.

Urinary Tract Anti Infective Agents Mechanism Of Action

• The mechanism of action of quinolones is through the inhibition of bacterial gyrase, an enzyme involved in DNA replication, recombination, and repair.
• By interfering with gyrase, quinolones arrest bacterial cell growth.
• The affinity of quinolones to metal ions seems to be an important prerequisite of their antibacterial activity: probably, quinolones bind to the DNA-gyrase complex via a magnesium ion.

Read and Learn More Medicinal Chemistry III Notes

Chemical Structures Of Some Commonly Used Fluoroquinolones

Structure-Activity Relationship

Position – 1:

• Earlier studies indicated that substitution at the N-l position is important for Anti-bacterial activity.
• QSAR analysis of a set of N-l allyl and alkyl derivatives suggested an optimum STERIMOL length of 0.42 nm, corresponding approximately to an ethyl group.

Position – 3:

• Position 3 and 4, having a link between the carboxylic acid and the keto groups are generally considered necessary for binding quinolones to DNA gyrase.
• Classical studies have produced no active quinolone with a significant modification of the C-3 carboxylic acid group, except groups that are converted in vivo to the carboxylic acid group.

Position – 4:

Position – 4 has not been extensively explored and the replacement of the 4- keto group with other groups has generally produced inactive or weakly active compounds.

Position – 5:

• Compounds with small substituents such as nitro, amino, halo, and alkyl groups have been synthesized. Among them, the C-5 amino group enhances absorption and tissue distribution, for example Sparfloxacin.
• The incidence of phototoxicity of Sparfloxacin is the lowest of the fluoroquinolones, because of the presence of the 5amino group, which counteracts the effect of the 8- 8-fluoro substituent.

Position – 6:

• Of various C-6 substituents, H, Cl, Br, F, Cl₁₂, S- CM₃, CO CH₂, CN, NO₂, etc the addition of a fluorine atom resulted in a dramatic increase in anti-bacterial potency.
• The Fluoro group at C-6 seems to improve both the DNA gyrase complex binding (2 to 17 folds) and cell penetration (1 to 70 folds) of the corresponding derivatives with no substitution at C-6.

Position – 7:

• C-7 piperazinyl group in addition to the C-6 fluorine substituent has anti-bacterial potency superior to that of earlier classical quinolones against both gram-positive and gram-negative bacteria.
• In general, quinolones with small or linear C-7 substituents I, Cl, Cl, NH₂-CH₂-O h-
  NH₂, NH- CH₃, and NH-NH₂) possess moderate to weak anti-bacterial activities.
• Various substitutions tried at the C-7 position are –
• substituted piperazinyl.
• substituted pyrrolidinyl
• substituted morpholinyl
• In general, the substitution of methyl at the C-4 position of the piperazinyl group enhances gram-positive anti-bacterial activity with a slight decrease in gram-negative activity.

Position – 8:

• C-8 fluoro or chloro derivatives are more active in vivo, owing to better oral absorption.
• Oxygen substituent at the C-8 position, where the substituent is part of the ring system has been shown to have better in vivo efficacy.
• C-8 methoxy or ethoxy group appears to increase the spectrum of activity.
• C-8 methoxy (gratifloxacin) has been shown to contribute significant activity against anaerobes.
• Synthesis OF Ciprofloxacin
• By -cyclopropyl-6-fluoro-4-oxo-7-(pi pertain-l-yl)-l, 4-dihydroquinoline -3-carboxylic add

Urinary Tract Anti Infective Agents Multiple Choice Question And Answers

Question 1. Ciprofloxacin is…

1. Fluoroquinolones
2. Trioxane
3. Guanidine Derivative
4. None

Answer: 1. Fluoroquinolones

Question 2. Fluoroquinolone act on…

1. DNA gyrase
2. Arabinogalactan
3. Cox
4. All

Fluoroquinolones

Answer: 1. DNA gyrase

Question 3. Nalidixic Acid Act on…

1. Glycolic Acid
2. DNA gyrase
3. Cox
4. All

Answer: 2. DNA gyrase

Urinary Tract Anti Infective Agents Short Question And Answers

Question 1.  Write the mode of action of Fluoroquinolones.
Answer:

The mode of action of Fluoroquinolones: The mechanism of action of quinolones is through the inhibition of bacterial gyrase, an enzyme involved in DNA replication, recombination, and repair. By interfering with gyrase, quinolones arrest bacterial cell growth.

Fluoroquinolones

Question 2.  Write the mode of action of pyrazinamide.
Answer:

The mode of action of pyrazinamide: PZA enters the cell wall of M. tuberculosis viva passive diffusion and it is converted to pyrazinoic acid (Active metabolite) by pyrazinamidase enzyme. Then later it inhibits mycobacterial fatty acid synthase-I enzyme and disrupts mycolic add synthesis needed for mycobacterium cell wall synthesis.

Question 3.  Write the adverse effect of Cycloserine.
Answer:

The adverse effects of Cycloserine: Peripheral Neuritis, Tremors, Psychotic, and Behavioral changes

Question 4. Write the adverse effect of isoniazid.
Answer:

The adverse effect of isoniazid: Peripheral neuritis-co administration of Pyridoxine (Vit B6) with INH prevents the symptoms of peripheral neuritis. GIT disturbance (Constipation, Loss of appetite) Hepatotoxicity

Question 5. Write the mode of action of Rifampicin.
Answer:

The mode of action of Rifampicin: It strongly binds to the p subunit of bacterial ‘DNA dependent RNA polymerase’ enzyme. Thereby inhibits the RNA synthesis of bacteria. Mammalian RNA polymerase does not bind to rifampicin.

Anti viral Agents Introduction

Anti virals are a class of medications that are used to treat viral infections. Most viral infections resolve spontaneously in immune-competent individuals.

• Antiviral therapy aims to minimize symptoms and infectivity as well as to shorten the duration of illness. These drugs act by arresting the viral replication cycle at various stages.
• Currently, antiviral therapy is available only for a limited number of infections.
• Most of the currently available antiviral drugs are used in the therapy of infections caused by HIV, herpes viruses, hepatitis Band C viruses, and influenza A and B viruses.
• Because viruses are obligate, intracellular parasites, it is difficult to find targets for the drug that interfere with viral replication without also harming the host cells.
• Unlike other antimicrobials, none of the antiviral drugs deactivate or destroy the microbe (in this case, the virus); rather they act by only inhibiting replication.
• Thus, they prevent the viral load from increasing to a point where it could cause pathogenesis, leaving it susceptible to neutralization by the body’s innate immune mechanisms.

Anti-Retroviral

1. Nucleoside reverse transcriptase inhibitors (NRTIs): Abacavir, Didanosine, Lamivudine, Stavudine, Tenofovir, Zalcitabine, Zidovudine, Emtricitabine

2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Delavirdine, Efavirenz, Nevirapine

3. Protease inhibitors: Nelfinavir, Amprenavir, Saquinavir, Ritonavir, Indinavir, Lopinavir, Atazanavir, Fosamprenavir, Tiranavir

4. Fusion inhibitors: Enfuvirtide

• Anti-Herpes Virus

Iodoxuridine, Acyclovir, Penciclovir, Famciclovir, Ganciclovir, Fomivirsen, Cidofovir, Valaciclovir, Foscarnet

• Anti-Influenza Virus

Amantadine, Rimantadine, Oseltamivir, Zanamivir

Read and Learn More Medicinal Chemistry III Notes

• Anti-Hepatitis B

Adefovir, dipivoxil, Entecavir

• Drugs For Other Viral Infections

Interferon a, Peginterferon a-2b, Ribavirin

1. Anti – Retroviral

 Nucleoside reverse transcriptase inhibitors (NRTIs):

NRTIs in the presence of host cell thymidine kinase convert into active triphosphate metabolite (nucleotides) → compete with corresponding nucleotide for incorporation into viral DNA → inhibit reverse transcriptase enzyme and termination of viral DNA synthesis.

Abacavir:

• Abacavir (ABC) is a powerful nucleoside analog reverse transcriptase inhibitor (NRTl) used to treat HIV and AIDS, Chemically
• it is a synthetic carbocyclic nucleoside and is the enantiomer with IS, 4R absolute configuration on the cyclopentene ring. In vivo, ab. David sulfate dissociates from its free base.

Didanosine:

A dideoxynucleoside compound in which the 3′-hydroxy group on the sugar moiety has been replaced by hydrogen.

• This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains.
• Didanosine is a potent inhibitor of HIV replication, acting as a chain-terminator of viral
• DNA by binding to reverse transcriptase is then metabolized to deoxyadenosine triphosphate, its putative active metabolite.

Lamivudine:

• Lamivudine is a Hepatitis B Vims Nucleoside Analog Reverse Transcriptase Inhibitor. The mechanism of action of lamivudine is as a Nucleoside Reverse Transcriptase Inhibitor.
• The chemical classification of lamivudine is the Nucleoside Analog Zalcitabine

Zidovudine:

 

A dideoxynucleoside compound in which the 3′-hydroxy group on the sugar moiety has been replaced by hydrogen.

• This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains.
• The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chain-terminator of viral DNA by binding to reverse transcriptase.
• Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy.

Zidovudine (AZT):

It is a thymidine analog and is also known as azidothymidine. It is converted into active triphosphate metabolite and incorporated in the viral DNA that inhibits reverse transcriptase enzyme and terminates the DNA chain synthesis.

• A dideoxynucleoside compound in which the 3′-hydroxy group on the sugar moiety has been replaced by an azido group.
• This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains.
• The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS.
• Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia.
• Zidovudine treatment significantly reduces the incidence of in-utero transmission of HIV from infected mother to fetus.
• Zidovudine and Stavudine are not used together because they appear to be antagonistic actions.

Adverse effects:

• All NRTIs show lactic acidosis, hepatic steatosis, and lipodystrophy (all higher with stavudine).
• Zidovudine: Bone marrow suppression-anemia, neutropenia; gastrointestinal intolerance, headache.
• Didanosin: pancreatitis, peripheral neuropathy, gastrointestinal intolerance.
• Stavudine: pancreatitis, peripheral neuropathy
• Tenofovir (diphosphonate diester of nucleoside): Headache, gastrointestinal intolerance, renal impairment.

Adverse effects:

• All NNRTI:
• Rash (most common) Rash can progress to Stevens-Johnson syndrome.
• Nevirapine: Hepatotoxicity, rash including Stevens-Johnson syndrome, induces the metabolism of protease inhibitors and oral contraceptives.

 Efavirenz:

• Neuropsychiatric reactions and teratogenic Protease inhibitors Protease inhibitors bind to the active site of protease enzyme → prevent the cleavage of gag-pol polyprotein → inhibit the maturation of virus resulting production of immature, non-infectious viral particles.
• The administration of Ritonavir with another PI is known as boosted therapy. All PI is metabolized in the liver and excreted in the fecal.

Adverse effects:

• All protease inhibitors: lip dystrophy (fat accumulation Fat redistribution- Buffalo Hump), hyperlipidemia, insulin resistance and diabetes, elevated liver function tests, inhibits metabolism of other protease inhibitors.
• Amprenavir, Fosamprenavir: Gastrointestinal intolerance, rash

D. Fusion inhibitors: Enfuvirtide

Fusion inhibitors gll20 and gP41 Enfuvirtide is a synthetic polypeptide and binds with viral surface glycoprotein 120 and 41 to inhibit the fusion of HIV with host cells (CD₄+ T helper cell) before the virus enters the cell and begins its replication process. Adverse reaction Injection site reaction, hypersensitivity reactions.

Anti-Herpes Virus:

Iodoxuridine, Acyclovir, Penciclovir, Famciclovir, Ganciclovir, Fomivirsen, Cidofovir, Valaciclovir, Foscarnet

Mechanism of action:

• Nucleoside analogs drugs in the presence of viral thymidine kinase are converted into mono phosphate nucleoside which converts into active triphosphate nucleotide active nucleotide inhibits the DNA polymerase and inhibits DNA synthesis.
• Foscarnet directly blocks DNA polymerase reverses transcriptase enzyme and inhibits DNA synthesis.

Anti Influenza Agent

Amantadine, Rimantadine, Oseltamivir, Zanamivir

Anti-Influenza Agent:

• Amantadine and Rimantadine prevent the uncoating of the influenza A virus and entry into the host cells.
• Oseltamivir and Zanamivir inhibit the neuraminidase (sialidase) in Influenza A and B → preventing the release of virions from host cells (spreading of virus).

Amantadine:

It is the organic compounds-adamantylamine or 1-amino adamantane, meaning it consists of an adamantane backbone that has an amino group substituted at one of the four methyne positions. Rimantadine is a closely related derivative of adamantane with similar biological properties.

1. Amantadine Mechanism of action: The mechanism by which Amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M₂ protein. In certain cases, Amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.
2. Rimantidine: Rimantadine is an orally administered antiviral drug used to treat, and in rare cases prevent, influenza virus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Both rimantadine and the similar drug amantadine are derivates of adamantane.

Rimantidine Mechanism Of Action: The mechanism of action of Rimantadine is not fully understood.

• Rimantadine appears to exert its inhibitory effect early in the viral replicative cycle, possibly inhibiting the uncoating of the virus.
• Genetic studies suggest that a virus protein specified by the virion M₂ gene plays an important role in the susceptibility of influenza A virus to inhibition by Rimantadine.

Oseltamivir:

• Oseltamivir is an antiviral medication that blocks the actions of influenza virus types A and B in your body.
• Oseltamivir is used to treat influenza in people 2 weeks of age and older who have had flu symptoms for 2 days or less.
• Oseltamivir may also be given to prevent influenza in people who are at least 1 year old, and who may be exposed but do not yet have symptoms.
• This medicine will not treat the common cold.

Oseltamivir Mechanism of Action: Oseltamivir inhibits the neuraminidase enzyme, which is expressed on the viral surface. The enzyme promotes the release of virus from infected cells and facilitates viral movement within the respiratory tract. In the presence of neuraminidase inhibitors, virions stay attached to the membrane of infected cells and are also entrapped in respiratory secretions.

Anti-Hepatitis B: Adcfovir, dipivoxil, Enlecavir

Drugs For Other Viral Infections: Interferon a, Peginterferon a-2b, Ribavirin

Synthesis Of Acyclovir

Anti viral Agents Multiple Choice Question And Answers

Question 1. Isoniazid is

1. Pyridine derivative
2. Trioxane derivative
3. Guanidine derivative
4. None

Answer: 1. Pyridine derivative

Question 2. Isoniazid act on

1. Mycolic acid
2. Arabino galactose
3. Cox V
4. All

Answer: 1. Mycolic acid

Question 3. Ethambutol act on

1. Mycolic acid
2. Arabino galactose
3. Cox
4. All

Answer: 2. Arabino galactose

Question 4. Neurotoxicity is the adverse effect of…

1. Isoniazid
2. Ethambutol
3. Both
4. None

Answer: 1. Isoniazide

Question 5.Visual disruption Adverse effect of

1. Isoniazid
2. Pyrazinamide
3. Ethambutol
4. None

Answer: 3. Ethambutol

Anti viral Agents Short Question And Answers

Question 1. Write the mode of action of isoniazid.
Answer:

Mode of action of isoniazid: INH inhibits Mycolase Synthase, an enzyme necessary for the biosynthesis of mycolic add (essential constitute of mycobacterial cell wall).

Question 2 Write the mode of action of pyrazinamide.
Answer:

Mode of action of pyrazinamide

• PZA enters the cell wall of M. tuberculosis via passive diffusion and it is converted to pyrazinoic acid (Active metabolite) by pyrazinamidase enzyme.
• Then later it inhibits mycobacterial fatty acid synthase-I enzyme and disrupts mycolic acid synthesis needed for mycobacterium cell wall synthesis.

Question 3 Write the adverse effect of Cycloserine.
Answer:

The adverse effect of Cycloserine

• Peripheral Neuritis
• Tremors
• Psychotic
• Behavioral changes

Question 4 Write the adverse effect of isoniazid.
Answer:

The adverse effect of isoniazid

• Peripheral Neuritis-Co administration of Pyridoxine (Vit B6) with INH prevents the symptoms of peripheral neuritis.
• GIT disturbance (Constipation, Loss of appetite)
• Hepatotoxicity

Question 5 Write the mode of action of Rifampicin.
Answer:

The mode of action of Rifampicin

• It strongly binds to the (3 subunit of bacterial ‘DNA dependent RNA polymerase’ enzyme.
• Thereby inhibits the RNA synthesis of bacteria. Mammalian RNA polymerase does not bind to rifampicin.

Question 6. Write the adverse of Rifampicin.
Answer:

tThe adverse of Rifampicin

• Hepatitis risk may increase when used in combination with INH.
• The flu-like syndrome is characterized by fever, chills, myalgias, and thrombocytopenia. Rifampicin imparts a harmless red-orange color to urine.

Anti Fungal Agents Introduction

Fungal infections are caused by eukaryotic organisms and for that reason, they generally present more difficult therapeutic problems than bacterial infections.

There are relatively few agents that can be used to treat fungal infections. The fungal cell wall may be considered to be a prime target for selectively toxic antifungal agents because No clinically available inhibitor of chitin synthesis analogous to the b-lactams exists at present, even though much effort is being directed toward developing such agents. Other targets are currently being exploited.

Classification Of Antifungal Agents

Polyenes:

Amphotericin B (Amb): It is obtained from Streptomyces nodosus. Amphotericin B is an amphoteric polyene macrolide (polyene = containing many double bonds; macrolide = containing a large lactone ring of 12 or more atoms) and gives fungicidal action.

• It is nearly insoluble in water (orally for topical infections), and is therefore prepared as a colloidal suspension of amphotericin B and sodium desoxycholate for intravenous injection (for systemic infections)

Mechanism of action: Amphotericin B binds with ergosterol (a component of the fungal cell membrane) → AMB- ergosterol complex alters the membrane permeability →creates pores in the membrane → pores allow the leakage of intracellular ions, amino acids, and micromolecules→ cell death.

Clinical uses: AMB is topically applied for oral, vaginal, and cutaneous candidiasis and partially used for systemic infections. AMB is the most effective drug for resistant cases of kala-azar.

Adverse effects: Infusion-related fever, chills, muscle rigor, and hypotension (histamine release) occur during i.v. infusion (a test dose is advisable) and can be alleviated partly by pretreatment with NSAIDs, antihistamines, meperidine, and adrenal steroids.

Greisofulvin:

• Heterocyclic benzofuran Greisofulvin
• It is isolated from Penicillium griseofulvum and cures infections due to dermatophytes (ringworm) when administered orally.
• It is ineffective against Candida albicans.

Greisofulvin Mechanism of action

• Griseofulvin interacts with microtubules of the mitotic spindle and with cytoplasmic microtubules →disorientation of mitotic microtubules and interferes in the mitosis → inhibits the growth of fungal hyphae.
• Griseofulvin has very low water-soluble damage → low absorption → absorption improved by taking it with fatty meals and microfinancing the drug particles.
• Now use ultrafine microparticles →increase Griseofulvin absorption and reduce to Vi dose compared to microfine particle formulations.

Greisofulvin Adverse Effect: Headache, GIT disturbances, peripheral neuritis, rashes, leukopenia.

Greisofulvin Interactions: Griseofulvin induces warfarin metabolism and reduces the efficacy of oral contraceptives.

Clotrimazole:

Clotrimazole Mechanism of action:

• Clotrimazole works by inhibiting tire growth of individual Candida or fungal cells by altering the permeability of the fungal cell wall.’ It binds to phospholipids in the cell
• membrane and inhibits the biosynthesis of ergosterol and other sterols required for cell membrane production.

Econazole

Econazole Mechanism of Action: Econazole interacts with 14-ct demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents.

Miconazole:

Miconazole inhibits the synthesis of ergosterol, a major component of fungal cell membranes. This interferes with the barrier function of the membrane and with membrane-bound enzymes.

Ketoconazole:

As an antifungal, ketoconazole is structurally similar to imidazole and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membranes, as well as certain enzymes. This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol.

Itraconazole:

The mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal-mediated synthesis of ergosterol, via the inhibition of lanosterol 14a demethylase.

Metabolites: Hydroxy-itraconazole, keto-itraco.

Fluconazole:

Mechanism of action:

Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14a-demethylase.

Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus

Naftifine:

Naftifine has a triple action: antifungal, antibacterial, and anti-inflammatory. Its precise mechanism of action is unknown but may involve selectively blocking sterol biosynthesis via inhibition of the squalene 2,3-epoxidase enzyme.

Tolfnatate:

Mechanism of action is not entirely known, it is believed to inhibit squalene epoxidase, an important enzyme in the biosynthetic pathway of ergosterol (a key component of the fungal membrane) in a similar way to allylamines.

Synthesis Of Miconazole

In hexamethylphosphoramide (an aprotic solvent) which was then extracted with nitric acid to give miconazole nitrate.

Synthesis Of Tolfnatate

Anti Fungal Agents Multiple Choice Question And Answers

Question 1.Griesofulvin is

1. Benzofurnn
2. Trioxane derivative
3. Guanidine Derivative
4. None

Answer: 1. Benzofurnn

Question 2.Gricsofulvin net on

1. Microtubule
2. Arabino galactose
3. Cox
4. All

Answer: 1. Microtubule

Question 3.Fluconazoleact on

1. Mycolic acid
2. Cytochrome P450 enzyme 14a-demethylase
3. Cox
4. None

Answer: 2. Cytochrome P450 enzyme 14a-demethylase

Question 4. Polyenesderivntive of…

1. Amphotericin
2. Ethambutol
3. Both
4. None

Answer: 1. Amphotericin

Anti-Fungal Agents Short Question And Answers

Question l. Write the mode of action of Griesofulvin.
Answer:

Mode of action of Griseofulvin: Griseofulvin interacts with microtubules of the mitotic spindle and with cytoplasmic microtubules → disorientation of mitotic microtubules and interferes in the mitosis→inhibits the growth of fungal hyphae.

Question 2. Write the mode of action of fluconazole.
Answer:

Mode of action of fluconazole: Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14a-demethylase.

Question 3. Write the adverse effect of amphotericin β.
Answer:

Adverse effect of amphotericin β: Infusion-related fever, chills, muscle rigor, and hypotension (histamine release) occur during i.v. infusion (a test dose is advisable) and can be alleviated partly by pretreatment with NSAIDs, antihistamines, meperidine, and adrenal steroids.

Anti Protozoal Agents Introduction

The antiprotozoal drug is any agent that kills or inhibits the growth of organisms known as protozoans. Protozoans cause a variety of diseases, including malaria and disease.

• While protozoans typically are microscopic, they are similar to plants and animals in that they are eukaryotes and thus have a clearly defined cell nucleus.
• This distinguishes them from prokaryotes, such as bacteria.
• As a result, many of the antibiotics that are effective in inhibiting bacteria are not active against protozoans.

Classification Of Antiprotozoal Drugs

Metronidazole: Metronidazole is one of the mainstay drugs for the treatment of anaerobic infections.

• It is approved by the US Food and Drug Administration for the treatment of anaerobic and protozoal infections.
• Metronidazole exerts its antimicrobial effects through the production of free radicals that are toxic to the microbe.

Mechanism Of Action: It inhibits nucleic acid synthesis by disrupting the DNA of microbial cells. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic bacteria and protozoans, it has relatively little effect on human cells or aerobic bacteria

Read and Learn More Medicinal Chemistry III Notes

Tinidazole:

Mechanism of Action: Tinidazole is an antiprotozoal, antibacterial agent. The nitro-group of tinidazole is reduced by cell extracts of Trichomonas. The free nitro-radical generated as a result of this reduction may be responsible for the antiprotozoal activity.

Mechanism of action: After passive absorption into the bacterium cells, the nitro group of imidazole is reduced to an amine group by ferredoxin-type redox systems.

Diloxanide:

Diloxanide destroys the trophozoites of E. history that eventually form into cysts. The cysts are then excreted by persons infected with asymptomatic amebiasis.

Iodoquinol:

Iodoquinol is an amebocyte used against Entamoeba histolytica, and it is active against both cysts and trophozoites that are localized in the lumen of the intestine. It is considered the drug of choice for treating asymptomatic or moderate forms of amebiasis.

Atovaquone:

Mechanism of action: Atovaquone selectively inhibits the malarial cytochrome complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential. Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidine synthesis.

Eflornithine:

Eflomithine prevents hair growth by inhibiting the anagen phase of hair production. This occurs by eflornithine irreversibly binding (also called suicide inhibition) to ornithine decarboxylase (ODC) and physically preventing the natural substrate ornithine from accessing the active site.

Synthesis Of Metronidazole

Anti Protozoal Agents Multiple Choice Question And Answers

Question 1. Isoniazid is …

1. Pyridine derivative
2. Trioxane derivative
3. Guanidine derivative
4. None

Answer: 1. Pyridine derivative

Question 2. Isoniazid act on

1. Mycolic acid
2. Arabino galactose
3. Cox
4. All

Answer: 1. Mycolic acid

Question 3. Ethambutol act on

1. Mycolic acid
2. Arabino galactose
3. Cox
4. All

Answer: 2. Arabino galactose

Question 4. Neurotoxicity is the adverse effect of…

1. Isoniazid
2. Ethambutol
3. Both
4. None

Answer: 1. Isoniazide

Question 5. Visual disruption Adverse effect of

1. Isoniazid
2. Pyrazinamide
3. Ethambutol
4. None

Answer: 3. Ethambutol

Anti Protozoal Agents Short Question And Answers

Question 1. Write the mode of action of isoniazid.
Answer:

Mode of action of isoniazid: INH inhibits Mycolase Synthase, an enzyme necessary for the biosynthesis of mycolic acid (essential constitute of mycobacterial cell wall).

Question 2. Write the mode of action of pyrazinamide.
Answer:

Mode of action of pyrazinamide: PZA enters the cell wall of M. tuberculosis via passive diffusion and it is converted to pyrazinoic acid (Active metabolite) by pyrazinamidase enzyme. Then later it inhibits mycobacterial fatty acid synthase-I enzyme and disrupts mycolic acid synthesis needed for mycobacterium cell wall synthesis.

Question 3. Write the adverse effect of Cycloserine.
Answer:

The adverse effect of Cycloserine

• Peripheral Neuritis
• Tremors
• Psychotic
• Behavioral changes

Question 4. Write the adverse effect of isoniazid.
Answer:

The adverse effect of isoniazid

• Peripheral Neuritis-Co administration of Pyridoxine (Vit B6) with INH prevents the symptoms of peripheral neuritis.
• GIT disturbance (Constipation, Loss of appetite)
• Hepatotoxicity

Question 5. Write the mode of action of Rifampicin.
Answer:

The mode of action of Rifampicin: It strongly binds to the (3 subunit of bacterial ‘DNA dependent RNA polymerase’ enzyme. Thereby inhibits the RNA synthesis of bacteria. Mammalian RNA polymerase does not bind to rifampicin.

Question 6. Write the adverse of Rifampicin.
Answer:

The adverse of Rifampicin

• Hepatitis risk may increase when used in combination with INH.
• The flu-like syndrome is characterized by fever, chills, myalgias, and thrombocytopenia.
• Rifampicin imparts a harmless red-orange color to urine.

Anthelmintics Introduction

The term anthelmintic is restricted to drugs acting locally to expel parasites from the gastrointestinal tract. Several types of worms penetrate other tissues, drugs that act on these parasitic infections are also known as anthelmintics.

The worm parasites of man belong to two phyla: Nemathelminthes (roundworms) and Platyhelminthes (flatworms). The roundworms include hookworm, whipworm, pinworm Strongyloides stercoralis, Trichinella spiralis, and Wuchereria bancrofti.

Anthelmintics Classification

Anthelmintics are classified based on their chemical structures.

• Piperazines: Example Diethylcarbamazine citrate, Piperazine citrate.
• Benzimidazoles: Example Albendazole, Mebendazole, Thiabendazole.
• Heterocyclics: Example Oxamniquine, Praziquantel.
• Natural products: Example Ivermectin, Avermectin.
• Vinyl pyrimidines: Example Pyrantel, Oxantel.
• Amide: Example Niclosamide.
• Nitro derivative: Example Niridazole.
• Imidazo thiazole: Example Levamisole.

Piperazines

Diethylcarbamazine:

Diethylcarbamazine Use: It is the drug of choice for filariasis (Wuchereria bancrofti, Brugia malayi, Acanthocheilonema perstans).

Read and Learn More Medicinal Chemistry III Notes

Benzimidazole:

Albendazole:

Albendazole Use: It is a new benzimidazole useful in the treatment of intestinal nematode infection and echinococcosis. It is effective against roundworm, hookworm, whipworm, and threadworm infestations. It is effective in the treatment of ascariasis.

Mebendazole:

Mebendazole Use: It is used in the treatment of hookworm, pinworm, roundworm, and whipworm infestation.

Heterocyclics:

Praziquantel:

Praziquantel Use: H is considered the drug of choice for the treatment of Schistosoma japonicum, (blood fluke) (intestinal flukes) clonorchiasis (Chinese liver fluke), and opisthorchiasis (liver fluke).

Anthelmintics Natural Products

Ivermectin:

Ivermectin is usually extracted from the soil of actinomycete Streptomyces avermitilis, the natural Ivermectins are 16- 16-membered macrocyclic lactones, with broad antinematocidal activity. It is a mixture of 22,23 – dihydro derivative of Avermectins Bla and Bib.

Ivermectin Use: Ivermectin is widely used in veterinary practice for the control of endoparasites and ectoparasites in domestic animals. It is also used to treat onchocerciasis in humans caused by roundworm Onchocerca volvulus

Vinyl Pyrimidines:

Vinyl Pyrimidines Use The anthelmintic choice in the treatment of hookworm, pinworm, and roundworm infestations.

Amide:

Niclosamide (Niclosan):

Niclosamide (Niclosan) The anthelmintic of first choice in the treatment of beef tapeworm, fish tapeworm, pork tapeworm, and dwarf tapeworm infestations.

Synthesis Of Mebendazole

Anthelmintics Multiple Choice Question And Answers

Question 1. Piper. vine citrate comes under which class of anthelmintics.

1. Heterocyclics
2. Benzimidazole
3. Piperazines
4. Natural product

Answer: 3. Piperazines

Question 2. Which one is the benzimidazole derivative

1. Praziquantel
2. Mebendazole
3. Suramin
4. All

Answer: 2. Mebendazole

Question 3. Which one is lmidazo Thiazole…

1. Albendazole
2. Mebendazole
3. Levcmasol
4. All

Answer: 3. Levcmasol

Question 4. Anthelmintics are used to irradicate…

1. Parasites
2. Helminth
3. Worms
4. All

Answer: 4. All

Anthelmintics Short Question And Answers

Question 1. What arc anlhelimlics or antihelmintics?
Answer:

Anthelmintics: The Ten anthelmintics are restricted to drugs acting locally to expel parasites from the gastrointestinal tract. Several types of worms penetrate other tissues, and drugs that act on these parasitic infections are also known as anthelmintics. Example: Albendazole.

Question 2. Write the use of Ivermectin…
Answer:

Use of Ivermectin: Ivermectin is widely used in veterinary practice for the control of endoparasite and exoparasite in domestic animals. It is also used to treat onchocerciasis in humans caused by roundworm Onchocerca volvulus.

Question 3. Write the use of Pirental…
Answer:

Use of Parental

Lrse of Pirental: The anthelmintic choice in the treatment of hookworm, pinworm, and roundworm infestations.

Sulphonamides And Sulfones Introduction

The sulfonamide drugs were the first effective chemotherapeutic agents to be employed systemically for the prevention and cure of bacterial (pyrogenic bacterial) infections in humans. Sulfonamide can be considered as derivatives of Para-aminobenzene sulfonamide (sulfanilamide).

• The S₂NH₂ group (Nl) is not essential and governs Solubility, Potency, and Pharmacokinetic properties.
• The para-NH₂ group (the N of which has been designated as N₄) is essential for anti-bacterial activity. Most of them are relatively insoluble in water, but their sodium salts are readily soluble.

Antimicrobial Activity

Antimicrobial activities of the sulfonamides depend on the substituent and their position in the benzene ring. Sulphonamides are bacteriostatic.

Read and Learn More Medicinal Chemistry III Notes

• The sulphonamide-sensitive micro-organisms require p-Amino benzoic acid (PABA) for the synthesis of folic acid which is essential for the synthesis of DNA and RNA.
• Due to the structural resemblance of sulphonamides with PABA, sulphonamides competitively inhibit PABA. This causes folic acid deficiency, resulting in arrest of bacterial growth and cell division

Classification Of Sulfonamide

Synthesis Of Sulfonamide

Some Examples Of Sulfonamide

Classification According To Mode Of Action Sulphonamides For General Infections

Sulphonamides For General Infections: Sulphanilamide (Prontosil album) (Protonsil is the first identified sulphonamide)

Sulphanilamide Use: Because of its high toxicity, it is not in practice now. But still used in veterinary practice as an antibacterial agent.

Sulphamethoxazole (Gantanol):

Sulphamethoxazole Use: It is used in the treatment of meningitis, and lower urinary tract infections caused by Escherichia coli and Proteus mirabilis.

Sulphonamides For Intestinal Infections: Sulphasalazine (Saaz, Salazar)

Sulphasalazine is a prodrug, which cleaved at the N4 position in the large intestine to m-Ammo salicylic acid and Sulphapyridine by azo reductase. Sulphapyridine acts as an antibacterial and aminosalicylic acid has an anti-inflammatory effect on the colon.

The advantage of this prodrug is the release of aminosalicylic acid, which prevents the absorption of the agent (prevents the systemic absorption) so that the duration of action increases (concentrates the drug in the active site). It is mainly used in intestinal infections

Sulphasalazine Use: It is used to treat ulcerative colitis and rheumatoid arthritis

Sulphonamides For Local Infections: A. Sulphacetamide (Setride, Zincoren) Sulfacetamide is a simple acetyl derivative of sulphanilamide, known as Albucid SO₂NHCOCH₃ N-sulphonyl acetamide

Use: Sulphacetamide sodium is used to treat infection or injuries of the eye.

Sulphonamide For Dermatitis: Dapsone (Dds) is Used in the treatment of leprosy and nocardiosis.

Sar Of Sulfonamide

The large numbers of synthetic antibacterial sulfonamides with their various modifications have permitted to investigation of the influence of structural alteration on the antibacterial activity. Since sulfonamides are rather small molecules (as shown in the key structure) and there aren’t too many variations that can be carried out without changing the basic nucleus, these have led to the following conclusions

The amino & Sulphonyl groups on the benzene ring are essential and should be in 1,4-position Replacement of the Aromatic ring by other ring systems or the introduction of additional substituents on it decreases or abolishes activity.

1. Exchange of the -SO₂NH group by -CO-NH reduces the activity.
2. Substitution of Aromatic Heterocyclic nuclei at N1- yields highly potent compounds.
3. N-Di substitution in general leads to inactive.

• 1-The (N4) amine and sulfonamide groups should be on the benzene ring in the 1,4 para positions for antibacterial activity. However, the N4 should be unsubstituted or substituted to form azo or amide prodrugs or new analogs. Prodrugs are inactive unless they can be hydrolyzed in vivo to regenerate the parent drugs.
• 2-Replacement of the benzene ring with another ring system or its substitution on position other than 1,4 position will decrease or abolish the antibacterial activity.
• 3-Exchanging the sulfonamide group SO₂NHR with the sulfone SO₂Ph-pNH₂ will retain the activity.
• The 4-Sulfonamide group is essential for biological activity and the amide should be secondary (Nl). The presence of p-aminobenzensulfonyl moiety has an important role in maintaining antibacterial activity.
• Therefore, all of the attention is focused on the Nl-substituents. These substituents seem to affect the physicochemical and pharmacokinetic characteristics of the drug. The already established substitution sites are:
• A- Nl substitution with various heteroaromatic and non-heteroaromatic (R”) influence the extent of plasma protein binding that in turn affects the drugs’ plasma concentration in addition to their onset and duration of action. Furthermore, the nature of the (R”)group influences the drug’s pka, its lipophilic-lipophobic solubility behavior, its excretion, and its toxicity profile. B- N₄ azo and acyl derivatives as prodrugs

Synthesis Of Trimethoprim

Synthesis Of Dapsone

Sulphonamides And Sulfones Multiple Choice Question And Answers

Question 1. Sulphonamides are derivative of…

1. Sulphanilamide
2. PABA
3. Sulpher
4. None

Answer:1. Sulphanilamide

Question 2. Short-acting Sulfonamide is

1. Sulfamethoxazole
2. Sulfadiazine
3. Sufapirazine
4. None

Answer: 2. Sulfadiazine

Question 3. Sufapirazine is …

1. Long-acting
2. Short-acting
3. Intermediate-acting
4. Special purpose

Answer: 4. Special purpose

Question 4. The mechanism of sulfonamide is inhibition of…

1. DNA Polymerase
2. PABA
3. Both
4. None

Answer: 2. PABA

Question 5. Sulfonamide inhibits PABA incorporation

1. Competitively
2. Non-Competitively
3. Proportionality
4. None

Answer: 1. Competitively

Sulphonamides And Sulfones Short Question And Answers

Question 1. Write the mode of action of Sulfonamide.
Answer:

The mode of action of Sulfonamide

Due to the structural resemblance of sulphonamides with PABA, sulphonamides competitively inhibit PABA. This causes folic acid deficiency, resulting in the arrest of bacterial growth and cell division.

Question 2. Write the SAR of sulfonamide.
Answer:

The SAR of sulfonamide

SAR of sulfonamide:

• The – SO₂NH₂ group (Nl) is not essential and governs Solubility, Potency, and Pharmacokinetic properties.
• The para-NH₂ group (the N of which has been designated as N₄) is essential for anti-bacterial activity.
• Most of them are relatively insoluble in water, but their sodium salts are readily soluble.

Question 3. Write the use of sulfonamide.
Answer:

The use of sulfonamide: Use of sulfonamide Because of its high toxicity it is not in practice now. But still used in veterinary practice as an antibacterial agent.

Drug Design Introduction

Drug discovery is the process through which potential new therapeutic entities are identified, using a combination of computational, experimental, translational, and clinical models.

• Despite advances in biotechnology and understanding of biological systems, drug discovery is still a lengthy, costly, difficult, and inefficient process with a high attrition rate of new therapeutic discovery.
• Drug design is the inventive process of finding new medications based on the knowledge of a biological target.
• In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the molecular target with which they interact and bind.
• Drug design frequently but not necessarily relies on computer modeling techniques and bioinformatics approaches in the big data era.
• In addition to small molecules, biopharmaceuticals and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also gained great advances.
• Drug development and discovery includes preclinical research on cell-based and animal models and clinical trials on humans, and finally move forward to the step of obtaining regulatory approval to market the drug.
• Modern drug discovery involves the identification of screening hits, medicinal chemistry, and optimization of those hits to increase the affinity, selectivity (to reduce the potential of side effects), efficacy or potency, metabolic stability (to increase the half-life), and oral bioavailability.
• Once a compound that fulfills all of these requirements has been identified, it will begin the process of drug development before clinical trials.

Factors Affecting Drug Discovery

Several factors affect the drug discovery and development process.

Important ones are as follows:

• Medicinal objective: In general, the more precise the medicinal objective, the less likely it is to develop a new drug; for example, it is easy to develop an antacid but much more difficult to develop a specific proton pump inhibitor. Thus, the medicinal requirements affect the likelihood of success or failure in new drug discovery.
• Ability of Medicinal chemist: The attributes of the chemist will influence the outcome of evolving new drugs based on knowledge of the chemistry of lead molecules and the biology of a diseased state.
• Screening Facilities: A successful and rapid mass screening mainly depends on the capacity to evaluate a large number of compounds and detect potentially clinically useful drugs in a very short period.
• Drug development facility: Good facilities with interdisciplinary efforts by chemistry, biology, pharmacy, and medical groups are necessary for drug development.

Cost Of New Drug

The following three factors affect the cost of drug development

• Number of compounds synthesized: Of the about 5000-10,000 compounds studied, only one drug reaches the market.
• Nature of the lead molecule: The cost of production will be high if the lead molecule is prepared by an expensive route.
•  Standards required for new drugs: The standards required by regulatory authorities before the release of a drug into the market have increased dramatically. In the discovery phase, each drug cost about $350 million. The Food and Drug Association processes I, II and III cost another $150 million. This brings the total to about $500 million for each drug put on the market for consumers.
• Due to these factors, the process of drug discovery is undergoing a complete overhaul to be cost-effective and to meet the supply and demand fundamentals.

Read and Learn More Medicinal Chemistry III Notes

Approaches For Drug Discovery

Evidence of the use of medicines and drugs can be found as far back in time as 3100 BC. The current scenario of the development of new drugs needs no emphasis in light of the current global situation of health and disease.

• For the majority of the time, drug discovery has been a trial-and-error process.
• Conventionally, the process of drug development has revolved around an almost blind screening approach, which was very time-consuming and laborious.
• The disadvantages of conventional drug discovery as well as the allure of a more deterministic approach to combat the disease have led to the concept of “Rational drug design”
  in the 1960’s. A new understanding of the quantitative relationship between structure and biological activity ushered in the beginning of computer-aided drug design (CADD).

How To Design A Drug?

At the onset, it is important to know what features an “ideal” drug should have. The drug

• Nowadays, after knowing the detailed information of the target and lead molecule, a drug is designed with the help of computer tools.
• This can potentially save pharmaceutical companies, government, and academic laboratories alike from pursuing the “wrong” leads.

Structure-Based Drug Design

Structure-based drug design (SBDD) is considered one of the most innovative and powerful approaches in drug design. SBDD is an iterative approach. It requires a three-dimensional (3D) structure of the target protein, preferentially complexed with a ligand, where binding mode, affinity, and confirmation of a ligand binding can be discerned.

• Subsequently, various methods are used to design a high-affinity inhibitor either via virtual computer screening of large compound libraries or through the design and synthesis of novel ligands.
• Designed compounds are then tested in appropriate assays and the information is further used to guide the SBDD.
• Recent advances in computational methods for lead discovery include various commercially available software for de novo drug design, iterative design, selectivity discrimination, and estimation of ligand-binding affinities.
• SBDD and the emergence of structural genomics are paving the way to develop designer drugs. Two approaches to SBDD, the docking of known compounds into a target protein and de novo drug design have been merging as a single robust and powerful tool.
• In addition, the dynamics simulation of multiple copies of molecular building blocks in the presence of a receptor molecule is also a useful strategy for drug design, In the future, SBDD will merge with high throughput and, informatics technologies such as bioinformatics to design drugs with multiple homologous targets simultaneously.

• Dynamic combinatorial chemistry is a recently introduced supramolecular approach that uses self-assembly processes to generate libraries of chemical compounds. In contrast to the stepwise methodology of classical combinatorial techniques, dynamic combinatorial chemistry allows for the generation of libraries based on the continuous interconversion between the library constituents.
• Spontaneous assembly of the building blocks through reversible chemical reactions virtually encompasses all possible combinations, and allows the establishment of adaptive processes owing to the dynamic interchange of the library constituents.
• The addition of the target ligand or receptor creates a driving force that favors the formation of the best-binding constituent- a self-screening process that is capable, in principle, of accelerating the identification of lead compounds for drug discovery.

Drug Design Based On Bioinformatics Toots

The processes of designing a new drug using bioinformatics tools have opened a new area of research. However, computational techniques assist one in searching drug targets and designing drugs in silico, but it is time-consuming and expensive.

• Bioinformatics tools can provide information about potential targets that include nucleotide and protein sequencing information, homologs, mapping information, gene and protein expression data, function prediction, pathway information, disease associations, variants, structural information, and taxonomic distribution among others.
• This means that time, effort, and money can be saved in characterizing different targets. The field of. bioinformatics has become a major part of the drug discovery pipeline, playing a key role in validating drug targets.
• By integrating data from many interrelated yet heterogeneous resources, bioinformatics can help in our understanding of complex biological processes and help improve drug discovery.

computer-Aided Drug Design

Computational tools have become increasingly important in drug discovery and design processes. Methods from computational chemistry are used routinely to study drug-receptor complexes in atomic detail and to calculate the properties of small-molecule drug candidates.

• Tools from information sciences and statistics are increasingly essential to organize and manage the huge chemical and biological activity databases that all pharmaceutical companies now possess and to make optimal use of these databases.
• In addition, the act of generating chemical derivatives is highly amenable to computerized automation. Libraries of derivative compounds are assembled by the application of targeted structure-based combinatorial chemistry from the analysis of active sites.
• Because of the combinatorial nature of this method, a large number of candidate structures may be possible. A computer can rapidly generate and predict the binding of all potential derivatives, creating a list of the best potential candidates. In essence, the computer filters all weak binding compounds, allowing the chemist to focus, synthesize, and test only the most promising ligands. Thus, using the CADD software to aid in the refinement of lead molecules is the most effective manner in which these tools can be employed.
• The use of computer modeling to refine structures has become standard practice in modern drug design. So the current role of computers in drug design lies in:

Storing and retrieving information:

• Structures determined experimentally by X-ray crystallography for biological targets (enzymes) and drug molecules
• Molecules and activities to test the effect of small structural changes on biological activity

Information about toxicity and its relationship to structure

Visualization of molecules:

• Similarities/differences between drugs and receptors
• Interaction between drugs and receptors

Calculations:

• Interaction strengths
• Motion (dynamics)

Challenges In Computer-Aided Drug Design

Highly intellectual professionals with interdisciplinary knowledge of various facets of science, most importantly, biology, chemistry, and computation are required for CADD and this is a major challenge for this field.

• In scientific computing, accuracy and processing time are always important. Thus, to make the calculations in a finite period, a plethora of assumptions, significant approximations, and numerous algorithmic shortcuts have to be used. This, in turn, greatly diminishes the calculated accuracy of any ligand-receptor interaction.
• This remains the most significant challenge in CADD. Another problem is the generation of a vast number of undesired chemical structures as there are a nearly infinite number of potential combinations of atoms and most of them are either chemically unstable, synthetically unfeasible, or have higher toxicity.
• Keeping in mind these shortcomings of CADD, improved generation of software with more user-friendly programs, superior and fast computational facilities, and creation of synthetic feasible and stable chemical compounds with refinement features have been developed in the last decade.

Drug Design Softwares

General Approach:

• The development of a new drug starts with the design of suitable candidate compounds, so-called “Ligands,” which are selected based on how the target protein recognizes these compounds and binds to them.
• “Ligbuild” is a powerful tool to build a legend just based on a protein structure in Brookhaven format. Performing experiments to know protein dynamics is expensive as well as time-consuming. The only alternative, computer simulation of the dynamics of the molecule (MD simulation), becoming increasingly important to identify which molecular properties are important and what are molecular interactions responsible for binding. Evaluation of binding agent is done by scoring approach.
• Score” is a tool to evaluate the binding affinity of protein-ligand complex with known 3D structure. Candidate molecules are further screened out on several criteria. Permeability across the biomembrane is an important characteristic.
• XLOGP can calculate logP (logarithm of the partition coefficient of a solute between octanol and water) of the common organic compounds, Furthermore, XLOGP can provide detailed hydrophobicity distribution information of the molecule.
• PLOGP can calculate logP values of peptides along with the Molecular Lipophilicity Potential (MLP) profile of a protein with a known structure. A database-based predictive system is also developed to assess the risk and toxicity of the chemicals in the early stage of drug design. The activity prediction studies based on the shape of the molecule include

1. 1. Fast and efficient clustering of molecules based on molecular shape
   2. Field-based similarity computation of molecular structure
   3. Flexible Quantitative Structure-Activity Relationships (QSAR) analysis of molecules based on shape cluster

• Comparative Molecular Field Analysis (CoMFA) has been widely used as a type of 3D QSAR method during the last 10 years.

Rational programs used: Drug design programs fall into one of three main categories: scanners, builders, or hybrids. Scanners-These types of programs are used for screening lead compounds. All database search programs fall into this category.

Rational programs used Strengths:

• Complete control of user on query specifications
• Established synthetic feasibility of compounds tested
• Rapid determination of potential binding ligands
• No scoring function is required

Rational programs used Weaknesses:

• The requirement for a wide database of structures
• Diversity of potential hits is limited as there is no recombination or derivatization of retrieved structures

Builders and Hybrids:

• These programs are mainly used for de novo generation of lead compounds. In these, the database contains fragments or chemical building blocks instead of complete compounds and requires the attachment point of the weak binding protein.
• It creates a population of derivatives with improved receptor complementarity by recombination or derivatization from fragments by making incremental changes iteratively.

Builders and Hybrids Strengths:

• No database of structures required
• Offers a vast number of potential derivative structures
• Creates truly novel ligands …

Builders and Hybrids Weaknesses:

• Questionable synthetic feasibility of compounds
• Generation of chemically unstable structures
• It depends mainly on the ability of the developer The software used
• Some of the frequently used software for drug design and their salient features are as follows:

Affinity:

• Automated, flexible docking
• Uses the energy of the ligand/receptor complex to automatically find the best binding modes of the ligand to the receptor (energy-driven method)

Auto Dock (Automated Docking of Flexible Ligands to Receptors):

• It consists of three separate programs: AutoDock performs the docking of the ligand to a set of grids describing the target protein AutoGrid precalculates these grids AutoTors sets up which bonds will be treated as rotatable in the ligand
• Provide an automated procedure for predicting the interaction of ligands with biomolecular targets and help to narrow the conformational possibilities and in the identification of the most suitable structure
• Uses a Monte Carlo (MC) simulated annealing (SA) technique for configurational exploration with a rapid energy evaluation using grid-based molecular affinity potentials
• A powerful approach to the problem of docking a flexible substrate into the binding site of a static protein
• It has applications in X-ray crystallography, SBDD, lead optimization, virtual screening, combinatorial library design, protein-protein docking, and chemical mechanism studies

Combibuild:

• Structure-based drug design program created to aid the design of combinatorial libraries
• Screens library possible reactants on the computer, and predicts which ones will be the
  most potent
• Successfully applied to find nanomolar inhibitors of Cathepsin D

Dock Vision: A docking package created by scientists for scientists by including Monte Carlo, Genetic Algorithm, and database screening docking algorithms

Fred:

• Accurate and extremely fast, multi-conformer docking program
• Examines all possible poses within a protein active site, filtering for shape complementarities and optional pharmacophoric features before scoring with more conventional functions

Flexi Dock:

• Simple, flexible docking of ligands into binding sites on proteins
• Fast genetic algorithm for the generation of configurations
• Rigid, partially flexible, or fully flexible receptor side chains provide optimal control of ligand binding characteristics
• Conformationally flexible ligands
• Tunable energy evaluation function with special H-bond treatment
• Very fast run times

Flexx:

• A fast computer program for predicting protein-ligand interaction
• Two main applications: Complex prediction (create and rank a series of possible
  protein-ligand complexes) Virtual screening (selecting a set of compounds for experimental testing)
• Conformational flexibility of the ligand; rigid protein
• Placement algorithm based on the interactions occurring between fhe molecules (limited to low-energy structures)
• MIMUMBA torsion angle database used for the creation of conformers; interaction geometry database used to exactly describe intermolecular interaction patterns
• Boehm function (with minor adaptations necessary for docking) applied for scoring

Glide:

• High-throughput ligand-receptor docking for fast library screening
• Fast and accurate docking program
• Identifies the best binding mode through Monte Carlo sampling
• Provides an accurate scoring function for ranking binding affinities
• Can enrich the fraction of suitable lead candidates in a chemical database by predicting binding affinity rapidly and with a reasonable level of accuracy-will greatly enhance the probability of success in a drug discovery program

Gold:

• Calculates docking modes of small molecules into protein binding sites Based on genetic algorithm for protein-ligand docking
• Studies full ligand and partial protein flexibility
  Predicts energy functions partly based on conformational and non-bonded contact information from the CSD
• Choice of scoring functions: GoldScore, ChemScore, and User-defined score
• Has virtual library screening

Hint:

• Hydropathic Interactions
• Empirical molecular modeling system with new methods for de novo drug design and protein or nucleic acid structural analysis
• Translates the well-developed Medicinal Chemistry and QSAR formalism of LogP and hydrophobicity into a free energy interaction model for all bimolecular systems based on the experimental data from solvent partitioning Calculates 3D hydropathy fields and 3D hydropathic interaction maps
• Estimates LogP for modeled molecules or data files

Conclusions:

• The development of new drugs with potential therapeutic applications is one of the most complex and difficult processes in the pharmaceutical industry.
• Millions of dollars and man-hours are devoted to the discovery of new therapeutic agents. As the activity of a drug is the result of a multitude of factors such as bioavailability, toxicity, and metabolism, rational drug design has been a utopia for centuries.
• Very recently, impressive technological advances in areas such as structural characterization of biomacromolecules, computer sciences, and molecular biology have made rational drug design feasible. CADD is no longer merely a promising technique.
• It is a practical and realistic way of helping the medicinal chemist. On its own, it is unlikely to lead to pharmaceutical novelties but it has become a significant tool, an aid to thought, and a guide to synthesis. Still, drugs that are synthesized and tested by computational techniques can contribute a clear molecular rationale and above all provide a spur to the imagination.

Quantitative Structure-Activity Relationship: QSAR is building a mathematical model correlating a set of structural descriptors of a set of chemical compounds to their biological activity.

QSAR Introduction:

QSAR involves the derivation of a mathematical formula that relates the biological activities of a group of compounds to their measurable physicochemical parameters. These parameters have a major influence on the drug activity. The QSAR-derived equation takes the general form Biological activity = function (parameters)

Activity is expressed as log (1/c). C is the minimum concentration required to cause a defined biological response.

QSAR Parameters:

• The parameter is the measure of the potential contribution of its, group to a particular property of the parent drug.
• Various parameters used in QSAR studies are
• Lipophilic parameters: partition coefficient, n-substitution constant.
• Polarizability parameters: molar refractivity, paracord
• Electronic parameters: Hammetconstant, dipole moment.
• Steric parameters: Taft’s constant.
• Miscellaneous parameters: molecular weight, geometric parameters.

Lipophilic Parameters: Lipophilicity is the partitioning of the compound between an aqueous and non-aqueous phase.

Partition coefficient:

P=[drug] in octanol/[drug] in water

• Typically over a small range of logP, for example, 1-4, a straight line is obtained.

Logl/C =0.75logP+2.30

• If the graph is extended to very high log P values, then get a parabolic curve

Logl/C=-kl (logP) ₂+k ₂logP+k3

• When P is small, dominated by log P term When P is large, log P squared dominates and so activity decreases
• substituent constant or hydrophobic substituent constants:
• The then-substituent constant is defined by Hanschand co-workers by the following equation.

Px= log Px-log PH

• A positive value indicates that the substituent has a higher lipophilicity than hydrogen and the drug favours the organic phase.
• A negative value indicates that the substituent has a lower lipophilicity than hydrogen and the drug favors the aqueous phase.

Electronic Parameters:

The Hammett Constant:

(σ); Sx= log (Kx/Kbenzoic)

• Equilibrium shifts Right and Kx – log Kbenzoic
• Since Sx= log Kx-log Kbenzoic, then s will be positive.
• Hammett constant takes into account both resonance and inductive effects; thus, the value depends on whether the substituent is para or meta-substituted Orthonot measured due to steric effects.

Steric Substitution Constant: It is a measure of the bulkiness of the group it represents and it affects the closeness of contact between the drug and receptor site. Much harder to quantify.

Examples are:

• Taft’s steric factor (Es) (1956), an experimental value based on rate constants
• Molar refractivity (MR)- a measure of the volume occupied by an atom or group equation includes the MW, density, and the index of refraction

Ver loopsteric parameter-computer program uses bond angles, van derwaals radii, bond lengths

Hansch Analysis:

Proposed that drug action could be divided into 2 stages:

1. Transport
2. Binding Each of these stages depends upon the physical and chemical properties of the drug.

Log1/c=k₁P=k₂P₂+k₂₃s+k₃Es+ks

• Look at the size and sign for each component of the equation. Values of 0.9 indicate the equation is not reliable Accuracy depends on using enough analogs, accuracy of data, and choice of parameters
• Applications: used to predict the activity of an as-yet unsynthesized analog.

Free Wilson Analysis:

This method is based on the assumption that the introduction of a particular substituent at a particular molecular position, always leads to a quantitatively similar effect on the biological potency of the whole molecules and is expressed by the equation.

Free Wilson Analysis Application:

• Easy to apply
• Simple method
• The substituent that cannot fulfill the principle of additivity can be recognized as effective when substituent constants are not available.

Topliss Method:

• This approach is completely non-mathematical and nonstatistical and does not need computerization of the data.
• A Toplissscheme is a flow diagram that in a series of steps directs the medicinal chemist to produce a series of analogs, some of which have greater activity than the lead used to start the 4 trees. There are two toplissschemes

1. 1. for the aromatic substituents
   2. for the aliphatic side chain substituents.

Topliss Method Applications: This method can be used if the synthetic route might be difficult and only a very few structures can be made in a limited time

Pharmacophore Modeling

Pharmacophore modeling is a successful yet very diverse subfield of computer-aided drug design. The concept of the pharmacophore has been widely applied to the rational design of novel drugs.

• In this paper, we review the computational implementation of this concept and its common usage in the drug discovery process.
• Pharmacophores can be used to represent and identify molecules on a 2D or 3D level by schematically depicting the key elements of molecular recognition. The most common application of pharmacophores is virtual screening, and different strategies are possible depending on the prior knowledge.
• However, the pharmacophore concept is also useful for ADME-tox modeling, side effects, and off-target prediction as well as target identification. Furthermore, pharmacophores are often combined with molecular docking simulations to improve virtual screening. We conclude this review by summarizing the new areas where significant progress may be expected through the application of pharmacophore modeling; these include protein-protein interaction inhibitors and protein design.

What is a pharmacophore?

• Historical perspective
• The original concept of the pharmacophore was developed by Paul Ehrlich during the late ISOOs.At that time, the understanding was that certain “chemical groups” or functions in a molecule were responsible for a biological effect, and molecules with similar effects had similar functions in common.
• The word pharmacophore was coined much later, by Schueler in his 1960 book Chemobiodynamics and Drug Design, and was defined as “a molecular framework that carries (phoros) the essential features responsible for a drug’s (pharmacon) biological activity.”
• The definition of a pharmacophore was therefore no longer concerned with “chemical groups” but “patterns of abstract features.”
• Since 1997, a pharmacophore has been defined by the International Union of Pure and Applied Chemistry as:
• A pharmacophore is the ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response.
• The pharmacophore should be considered as the largest common denominator of the molecular interaction features shared by a set of active molecules. Thus a pharmacophore does not represent a real molecule or a set of chemical groups but is an abstract concept.
• Despite this clear definition, the term pharmacophore is often misused by many in medicinal chemistry to describe simple yet essential chemical functionalities in a molecule (such as guanidine or sulfonamides), or common’ chemical scaffolds (such as flavones or prostaglandins).
• Often the long definition is simplified to “A pharmacophore is the pattern of features of a molecule that is responsible for a biological effect,” which captures the essential notion that a pharmacophore is built from features rather than defined chemical groups.

Future Perspectives On Pharmacophore Modeling

Pharmacophore modeling has been around since the beginning of CADD and has evolved from a basic concept into a well-established CADD method with applications including similarity metrics, virtual screening, ligand optimization, scaffold hopping, target identification, and so on.

• Given the simplicity and versatility of the pharmacophore concept, it can be anticipated that further developments will be made in the future for different applications.

Fragment-Based Drug Design

Over the last two decades, fragment-based drug design has become a well-established method for the rational development of novel drugs. Rather than screening drug-like molecules (with molecular weights of around 500 Da), smaller molecules with a molecular weight of up to 350 Da (referred to as fragments) are being screened for affinity with a receptor using susceptible biophysical methods.

• Fragments showing some affinity for the target are grown into bigger and more potent compounds, and fragments binding to adjacent areas can be linked as well.
• Since the diversity of small molecule fragments can easily be sampled with a few hundred compounds, in silico screening methods are highly suitable for fragment-based design.
• CADD methods such as docking and pharmacophore modeling have therefore also been used to identify fragment-like compounds in silico before testing in vitro; subsequent fragment recombination can be used for the de novo design of inhibitors.
• In the first approach, the starting point is a single pharmacophore query that spans two (qr^^ more) sub-pockets in the receptor binding site. An additional pharmacophore feature is added that does not represent a molecular recognition feature but represents an atom in the fragments, where the two fragments of the different pockets may overlap and be linked.
• Then fragments are identified that fulfill the features present in a sub-pocket of the pharmacophore query, as well as on the linking feature.
• Then the compatibility of the fragment hits for the respective sub-pockets is evaluated in terms of the possibility of maintaining the correct conformation after linking the two fragments. Subsequently, the de novo-designed compounds can be synthesized and evaluated.
• In the following example, using a different yet similar strategy, Cavalluzzo et al designed a novel small molecule inhibitor binding to the LEDGF p75 protein, based on an inhibitory peptide.
• They used predefined amino acid side chain fragments taken from the inhibitory peptide and constructed a pharmacophore query to link the two predefined fragments with a third scaffold fragment that mimicked similar interactions as the peptide.
• All possible compounds were enumerated virtually, and for the compounds that were able to adopt a conformation similar to the pharmacophore query after linking all fragments, the chemical synthesizability was assessed. Following synthesis, the inhibitory potency of the compound was found to be 30 pM IC50 compared to 7.4 pM IC50 for the most potent inhibitory peptide.
• Even when active fragments have been identified using the classical in vitro methods, computational pharmacophore methods can be applied to identify novel derivatives.
• For example, pharmacophore fingerprint-based similarity searching and the generation of 3D pharmacophore queries are suitable means to identify bigger and more potent molecules from small molecule libraries.

Protein-protein interaction (PPI) inhibition:

Although once thought to be undruggable, “high-hanging fruits on the drug discovery tree/’ PPIs have drawn a great deal of attention in recent years. The undruggable image has disappeared, and several small molecule inhibitors of PPIs (SMPPII) have been reported. Most of the early inhibitors originate from HTS.

• Structural analysis of proteins in PPI complexes and inhibitor complexes shows that the interactions at the PPI interface are being mimicked by the ligand.
• SMPPII are found to copy the natural interaction not only in terms of shape and chemistry but even at the electrostatic potential level. This mimicry suggests that the pharmacophore queries created from PPI complex structures can be used to identify SMPPII via virtual screening. Different methods can be employed to map the pharmacophore features onto the amino acids present at the PPI interface.
• Several SMPPII discoveries have been achieved, thanks to pharmacophore searches using manually created search features, a consensus of interactions at the PPI interface, or using automated methods, or by identification of the key interactions using molecular interaction field analysis.
• PPIs are especially promising targets for controlling inappropriate signaling, as found in diseases such as cancer. The usefulness of pharmacophore modeling to create queries encoding the key interactions at the PPI interface will probably strongly stimulate the discovery of novel SMPPII using pharmacophores, both as a stand-alone virtual screening tool and incorporated into pipelines with other methods

A potential role in protein design?

Although pharmacophore modeling originated as a drug design concept and, as indicated earlier, is nowadays a key element of CADD, pharmacophore modeling shows promise in the currently burgeoning field of computational protein design.

• Rather than designing drugs for a given protein target, computational protein design aims to derive an amino acid sequence that will fold into a given structure with a desired function.
• In many cases, this may involve protein-small molecule ligand interactions, and for these, it can easily be imagined that pharmacophores may be used simply by reversing the process of small molecule drug design for a known protein structure.
• First of all, suitable protein templates (enzymes or otherwise) should be identified for the protein redesign process. The ligand of interest could serve as a query to try to identify possible binding proteins, which can then later be redesigned to give optimum complementarity to the ligand.
• Second, during the virtual protein design process, often multiple rotamers of different amino acids are sampled to identify the most desirable ones.
• Similar to ligand fitting with a pharmacophore query, the protein side chains can be fitted to features describing the complementary interactions required at the protein-ligand interface.

Importance

• The pharmacophore concept was first put forward as a useful picture of drug interactions almost a century ago, and with the rise in computational power over the last few decades, has become a well-established CADD method with numerous different applications in drug discovery.
• Depending on the prior knowledge of the system, pharmacophores can be used to identify derivatives of compounds, change the scaffold to new compounds with a similar target, virtual screen for novel inhibitors, profile compounds for ADME-tox, investigate possible off-targets, or just complement other molecular methods.
• While there are limitations to the pharmacophore concept, multiple remedies are available at any time to counter them. Given this versatility, it is expected that pharmacophore modeling will maintain a dominant role in CADD for the foreseeable future, and any medicinal chemist should be aware of its benefits and possibilities.

Drug Design Multiple Choice Question And Answers

Question 1. The full form of CADD is.

1. Central Approach to Drug Design
2. Command Attribute for Drug design
3. Computer-Aided Drug Design
4. None

Answer: 4. None

Question 2. What is the full form of SBDD?

1. Software-Based Drug Design
2. Structure-Based Drug Design
3. Sample-Based Drug Design
4. None

Answer: 3. Sample-Based Drug Design

Drug Design Short  Question And Answers

Question 1. What is Drug design?
Answer:

Drug design: Drug design is the inventive process of finding new medications based on the knowledge of a biological target.

• In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the molecular target with which they interact and bind.
• Drug design frequently but not necessarily relies on computer modeling techniques and bioinformatics approaches in the big data era.

Question .2 Write the Ideal characteristics of a Drug.
Answer:

The Ideal characteristics of a Drug

• The ideal characteristics of a drug are.
• Must be safe and effective
• Should be well absorbed orally and bioavailable
• Metabolically stable and with a long half-life
• Nontoxic with minimal or no side effects
• Should have selective distribution to target tissues

Question .3 What is QSAR?
Answer:

QSAR:  QSAR involves the derivation of a mathematical formula that relates the biological activities of a group of compounds to their measurable physicochemical parameters. These parameters have a major influence on the drug’s activity.

• Chapter 1 Antibiotics Notes
• Chapter 2 Amino Glycosides
• Chapter 3 Tetracyclines
• Chapter 4 Macrolide Antibiotics
• Chapter 5 Prodrugs
• Chapter 6 Anti Malarial Agents Notes
• Chapter 7 Anti-Tubercular Agents Notes
• Chapter 8 Urinary Tract Anti-Infective Agents Notes
• Chapter 9 Antiviral Agents
• Chapter 10 Anti-Protozoal Agents Notes
• Chapter 11 Anthelmintics Notes
• Chapter 12 Sulphonamides and Sulfones Notes
• Chapter 13 Drug Design Notes 
• Chapter 14 Combinatorial Chemistry
• Chapter 15 Anti viral Agents And Anti Fungal Agents Notes