Prodrugs Introduction

An inactive precursor of a drug is converted into its active form in the body by normal metabolic processes. Prodrugs are used when drugs have unattractive physicochemical properties.

• Prodrugs are reversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect.
• In both drug discovery and development, prodrugs have become an established tool for
  improving the physicochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically active agents. ,
• About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend.
• The applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design and highlights examples of prodrugs that are either launched or are undergoing human trials.

Prodrugs Undesirable Properties

Physical Properties Poor

• aqueous solubility Low
• lipophilicity Chemical
• instability Pharmacokinetic
• Properties
• Poor distribution across biological membranes
• Good substrate for first-pass metabolism
• Rapid absorption or excretion when long-term effect desired
• Not site-specific

Prodrugs Can Be Classified Into Two Major Types, Based On How The Body Converts The Prodrug Into The Final Active Drug Form.

Type I prodrugs are bioactivated intracellularly: Examples of these are antiviral nucleoside analogs and lipid-lowering statins.

Type II prodrugs are bioactivated extracellular: Especially in digestive fluids or in the body’s circulation system, Examples of these are antibody, gene, or virus-directed enzyme prodrugs [ADEP/GDEP/ VDEP] used in chemotherapy or immunotherapy.

Some examples of Prodrug :

Carisoprodol is metabolized into meprobamate. Carisoprodol was not a controlled substance in the United States.

• However, meprobamate was classified as a potentially addictive controlled substance that can produce dangerous and painful withdrawal symptoms upon discontinuation of the drug.
• Enalapril is bioactivated by esterase to the active enalaprilat.
• Valaciclovir is bioactivated by esterase to the active aciclovir.
• Fosamprenavir is hydrolysed to the active amprenavir.
• Levodopa is bioactivated by DOPA decarboxylase to activate dopamine.
• Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol because pure chloramphenicol does not dissolve in water.
• Psilocybin is dephosphorylated to the active psilocin.
• Heroin is deacetylated by esterase to the active morphine.
• Molsidomine is metabolized into SIN-1 which decomposes into the active compound nitric oxide.
• Paliperidone is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone.
• Prednisone, a synthetic corticosteroid drug, is bioactivated by the liver into the active drug prednisolone, which is also a steroid.
• Primidone is metabolized by cytochrome 450 enzymes into phenobarbital, which is major, and phenylethylmalonamide, which is minor.
• Dipivefrine, given topically as an anti-glaucoma drug, is bioactivated to epinephrine.
• Lisdexamfetamine is metabolized in the small intestine to produce dextroamphetamine at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorder
• Diethylpropion is a diet pill that does not become active as a monoamine releaser or reuptake inhibitor until it has been Ndealkylated to ethylpropion.
• Fesoterodine is an antimuscarinic that is bioactivated to 5 hydroxymethyl tolterodine, the principal active metabolite of tolterodine.
• Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA).

Steps In Prodrug Design

Identification of drug delivery problem

• Identification of desired physic-chemical properties
• Selection of transport moiety which will give prodrug desired transport properties to be readily cleaved in the desired biological compartment

Depending upon the Nature of the Carrier used, the Carrier Linked prodrug Further Be Classified Into

Double prodrugs: pro-prodrugs, or cascade-latentiated prodrugs, where a prodrug is further derivatized in a fashion such that only enzymatic conversion to prodrug is possible before the latter can cleave to release the active drug.

1. Macromolecular prodrugs: where macromolecules like polysaccharides, dextrans, cyclodextrins, proteins, peptides, and polymers are used as carriers.

2. Site-specific prodrugs: where a carrier acts as a transporter of the active drug to a specific targeted site.

3. Mutual prodrug:

• • Where the carrier used is another biologically active drug instead of some inert molecule A mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a moiety for the other agent and vice versa.
  • The carrier selected may have the same biological action as that of the parent drug and thus might give synergistic action, or the carrier may have some additional biological action that is lacking in the parent drug, thus ensuring some additional benefit.
  • The carrier may also be a drug that might help to target the parent drug to a specific site or organ or cells or may improve the site specificity of a drug. The carrier drug may be used to overcome some side effects of the parent drugs as well.

Criteria For Prodrug

A well-designed carrier-linked prodrug should satisfy certain criteria. The linkage between the drug and the carrier should usually be a covalent bond.

• As a rule, the prodrug itself should be inactive or less active than the parent drug.
• The linkage should be reversible. The prodrug and the earner released after an in vivo enzymatic or non-enzymatic attack should be nontoxic.
• The generation of active form must take place ‘with rapid kinetics to ensure effective drug levels at the site of action.
• The bioavailability of cancer-linked prodrug is modulated by using a transient moiety.
• The lipophilicity is generally the subject of profound alteration of the parent molecule.
• The bioactivation process is exclusively hydrolytic and sometimes a redox system. An ideal carrier should be without intrinsic toxicity.
• It should be nonimmunogenic and non-antigenic and should not accumulate in the body.
• It should possess a suitable number of functional groups for drag attachment and adequate loading capacity.
• It should be stable to chemical manipulation and autoclaving.
• It should be easy to characterize and should mask tire liganded drag’s activity until the release of active agent at the tire’s desired site of action.
• In the mutual prodrug approach, the carrier should have some biological activity of its own.

Applications Of Prodrug

Prodrug to Improve Patient Acceptability:

• One of the reasons for poor patient compliance, particularly in the case of children is the bitterness, acidity, or causticity of the drag. Two approaches can be utilized to overcome the bad taste of drag. The first is the reduction of drag solubility in saliva and the other is to lower the affinity of drag towards taste receptors.
• Chloramphenicol has a bitter taste, so it is not well accepted by children. The pa Imitate ester of it is less soluble in saliva, so it masks the bitter taste.
• Several drags (NSAIDS, Nicotinic acid, Kanamycin, Diethylstilboestrol) cause irritation and damage to the gastric mucosa.
• Examples of prodrugs designed to overcome such problems of gastric distress are below (Aspirin & INH).

Prodrug to Improve Stability:

• Many drugs are unstable and may either break down on prolonged storage or are degraded rapidly on administration.
• Several drugs may decompose in GIT when used orally. Although enteric coatings may be used, it is also possible to utilize prodrug design to overcome this problem.
• An anti-neoplastic drug Azacytidine hydrolyses readily in acidic pH, but the bisulfite prodrug is more stable.

Prodrug to improve absorption: Ampicillin a wide-spectrum antibiotic is readily absorbed orally as the inactive prodrug, Pivampicillin, Bacampicillin, and Talampicillin which are then converted by enzymatic hydrolysis to Ampicillin.

A prodrug for slow release (sustained drug action):

• A common strategy in the design of slow-release prodrugs is to make long-chain aliphatic esters because these esters hydrolyze slowly and inject intramuscularly.
• Fluphenazine has a shorter duration of action (68h), but the prodrug Fluphenazine deconate has a duration of activity of about a month.

1. Prodrug to Improve Membrane Transport: Dopamine used for the treatment of Parkinson’s disease can be improved by administering its prodrug 3,4-dihydroxy phenylalanine (Levodopa).
2. Prodrug for Prolonged Duration of Action: Nordazepam, a sedative drug loses activity quickly due to metabolism and excretion. A prodrug Diazepam improves the retention characteristics, due to the presence of N- methyl group.

Prodrugs Short Question And Answers

Question .1 What are the mutual prodrugs?
Answer:

The mutual prodrugs: Where the carrier used is another biologically active drug instead of some inert molecule a mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a moiety for the other agent and vice versa.

Question . 2 Write the steps of designing of prodrug.
Answer:

The steps of designing of prodrug

• Identification of drug delivery problem
• Identification of desired physic-chemical properties
• Selection of transport moiety which will give prodrug desired transport properties to be readily cleaved in the desired biological compartment.

Tetracycline Introduction

Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of Streptomyces bacteria or produced semi-synthetically from those isolated compounds.

Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C, and D) to which a variety of functional groups are attached

Tetracycline Mode Of Action

The antimicrobial activity of tetracyclines reflects reversible binding to the bacterial 30S ribosomal subunit, specifically at the aminoacyl-tRNA acceptor (“A”) site on the mRNA ribosomal complex, thus preventing ribosomal translation Adverse Effect discoloration of teeth, kidney damage (Fanconi syndrome)

Chemistry Of Tetracycline

Carbon atom 4,4a, 5, 5a, 6 and 12a are potentially chiral.

• Oxytetracycline and doxycycline each with 5-OH substituents have six asymmetric centers while others have only five.
• The basic ring present in Tetracycline is polycyclic naphthalene carboxamide.
• All Tetracycline is amphoteric.
• At pH-7, it is converted into Zwitter-ion.

Ability to undergo epimerization at C₄ in a solution of neutral pH range

Tetracycline Classification

 

 

Tetracycline Contraindication

Tetracycline forms a chelate complex with many metals like calcium, magnesium, and iron.

• Chelates are usually insoluble in water which impairs the absorption of tetracycline in the presence of milk, Ca, Mg, and A α-containing antacids.
• The affinity of tetracycline for calcium causes them to be incorporated into newly forming bones and teeth as a tetracycline-calcium orthophosphate complex.
• Deposition of these antibiotics in teeth causes yellow discoloration.
• In pregnancy, Tetracycline is distributed into the milk of the lactating mother and it crosses the placental barrier into the fetus hurting the bones and teeth of a child.

Sar Of Tetracycline

Tetracyclines are composed of a rigid skeleton of 4 fused rings. The ring structure of tetracyclines is divided into an upper modifiable region and a lower non-modifiable region.

• An active tetracycline requires a C₁₀ phenol as well as a C₁₁-C₁₂ keto-enol substructure in conjugation with an OH group and a C₁-C₃ diketo substructure. Removal of the dimethylamine group at C4 reduces antibacterial activity.
• Replacement of the carboxylamine group at C₂ results in reduced antibacterial activity but it is possible to add substituents to the amide nitrogen to get more soluble analogs like the prodrug lymecycline.
• The simplest tetracycline with measurable antibacterial activity is 6-deoxy 6- demethyltetracycline and its structure is often considered to be the minimum pharmacophore for the tetracycle class of antibiotics can be modified to make derivatives with varying antibacterial activity

Tetracycline Multiple Choice Question And Answers

Question 1. The adverse effect of tetracycline is…

1. Gray baby syndrome
2. Fanconi syndrome
3. Ototoxicity

Red Man syndrome

Answer: 2. Fanconi syndrome

Question 2. Tetracycline act on…

1. 50s position
2. 30s position
3. Both
4. None

Answer: 2. 30s position

Question 3. Epimerization in tetracycline takes place at…

1. 3 position
2. 4 position
3. 5 position
4. 6 position

Answer: 2. 4 position

Question 4. Yellow discoloration of teeth is caused by …

1. Chloramphenicol
2. Amino glycoside
3. Tetracycline
4. Macrolide

Answer: 3. Tetracycline

Question 5. Photo Toxicity is the adverse effect of…

1. Chlortetracycline
2. Rolitetracycline
3. Demeclocycline
4. Doxycycline

Answer: 3. Demeclocycline

Tetracycline Short Question And Answers

Question 1. Classify natural tetracycline.
Answer:

Natural tetracycline: Chlortetracycline, Tetracycline, Oxytetracycline, Demeclocylin

Question 2. Write the name of the semi-synthetic tetracycline.
Answer:

The name of the semi-synthetic tetracycline: Minocycline, Lymecycline, Rolicycline, Clomocycline, Methacycline

Question 3. What is the mode of action of tetracycline?
Answer:

The mode of action of tetracycline: The antimicrobial activity of tetracyclines reflects reversible binding to the bacterial 30s ribosomal subunit, specifically at the aminoacyl-tRNA acceptor (“A”) site on the mRNA ribosomal complex, thus preventing ribosomal translation.

Question 4. What position is responsible for epimerization in tetracycline?
Answer:

C4 position.

Question 5. What is zwitter ion?
Answer:

Zwitter ion: The compounds contain both charges in their structure.

Macrolide Antibiotics Introduction

Macrolides belong to one of the most commonly used families of clinically important antibiotics used to treat infections caused by Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumonia, and Streptococcus pyogenes.

Chemically, macrolides are represented by a 14-, 15- or 16-membered lactone ring carrying one or more sugar moieties and additional substitutions linked to various atoms of the lactone ring

Macrolide Antibiotics Mechanisam Of Action

Bind to 50s subunit of ribosome causing them to dissociate from the mRNA resulting in premature termination of the amino acid chain and cessation of protein synthesis.

Macrolide Antibiotics Classification

Pharmacokinetics

Tacrolidc antibiotics are fairly absorbed from the gastrointestinal tract They penetrate moot tissues and host cells excellently. The concentrations in phagocytic cells exceed peach maximum serum levels by several folds.

• On me other hand, macrolides penetrate poorly into the brain, synovial fluid, and fetal tissues, macrolide antibiotics are excreted into mucosal fluid, breast milk, bile, and urine. The ratio of urinary or fecal excretion is variable.
• The portion of macrolide antibiotics excreted into bile is partially reabsorbed in the gut enterohepatic circulation,) Some drug is metabolized in the liver as well.

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Spectrum of Activity

• Active against give bacilli and give cocci
• Also active against H-Influenza, mycoplasma pneumonia, N.Gonorrhoea, and legionella

Chemistry Of Macrolides

The commercial product is Erythromycin A which is different from Erythromycin B in having -OH group at 12 position of aglycon.

• Erythronolide-Aglycon part of Erythromycin
• Glycon part-1. Basic ring-Desosamine 2. Neutral ring-cladinose While in the case of Erythromycin C, it has Mycarose as a neutral glycogen part instead of Cladinose
• It acts as an Enzyme inhibitor (Cyto-P-450 oxidase) for other drugs.
• Like Theophylline, Hydroxy coumarine, Benzodiazepine (Alprazolam, Midazolam), carbamazepine. Cyclosporine is an antihistaminic drug While the activity of terfenadine and astemizole is potentiated by Erythromycin.
• The stability of Erythromycin is at or neutral pH (7)
• Clarithromycin-6-methyl ether derivative of Erythromycin. (6-OH group is methylated to 6-OCH₃).
• It acts as an Enzyme inhibitor (Cyto-P-4aO oxidase) for other drugs.
• Specifically used to treat Lyme disease caused by Borrelia Burdorferi.
• Azithromycin, prepared by Beckmann rearrangement of 9-Oxime followed by N-methylation and reduction of resulting ring-expanded lactam. Nitrogen-containing 15-membered rings Macrolide is known as Azalides.
• It does not act as an enzyme inhibitor (Cyto-P-450 oxidase) for other drugs.
• Removal of 9-keto group-increasing stability of azithromycin to acid-catalyzed degradation. These changes also increase lipid solubility.
• Dirithromycin-Having 9N, 11 O-Oxazine ring

Sar

Chloramphenicol

Chloramphenicol is a broad-spectrum antibiotic with bacteriostatic activity and a wide spectrum of activity but is currently a backup drug for infections due to Salmonella typhi, B. fragilis, Rickettsia, and possibly bacterial meningitis.

• It was initially obtained from Streptomyces Venezuela
• Chloramphenicol has a broad spectrum of activity resembling that of the tetracyclines except that it exhibits a bit less activity against some gram-positive bacteria.
• It contains chlorine and is obtained from an actinomycete, and thus, named Chloromycetin.
• It is specifically recommended for the treatment of serious infections caused by H. influenza, S. typhi (typhoid), S. pneumoniae, and N. meningitides.
• Its ability to penetrate the CNS presents an alternative therapy for meningitis and exhibits anti-rickettsial activity.

Chloramphenicol The adverse effects: Chloramphenicol causes bone marrow depression and fatal blood dyscrasias.

Chloramphenicol Properties:

• Chloramphenicol is a white or greyish-white or yellowish-white crystalline powder or fine crystals, slightly soluble in water, soluble in alcohol, and propylene glycol.
• It was the first and still is the only therapeutically important antibiotic to be produced in competition with microbiological processes.
• It contains a nitrobenzene moiety and is a derivative of dichloroacetic acid. Since it has two chiral centers, four isomers are possible.
• The D is the biologically active form.

Chloramphenicol Mechanisam Of Action

• Chloramphenicol is a bacteriostatic by inhibiting protein synthesis.
• It prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome.
• It specifically binds to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit, preventing peptide bond formation.
• Chloramphenicol palmitate Prodrug is designed to mask the bitter taste
• Chloramphenicol succinate Prodrug designed to increase water solubility

Chloramphenicol Adverse Effects

• Dose-dependent bone marrow suppression is common
• Aplastic anemia is rare (1 in 35, 000).
• Gray baby syndrome in neonates (decreases glucuronysyl transferase)
• Optic neuritis in children.
• Broad spectrum antibiotic
• Nowadays, it is prepared by synthetic route from p-Nitro acetophenone.

Chemistry of chloramphenicol:

• It has two chiral carbons, so a total of four (4) isomers are possible D-erythro,  L-L-erythro, D-threo, and L-threo.
• Among these four isomers, the D-three isomer is the most active. The prodrug of Chloramphenicol viz., Chloramphenicol palmitate (USP) which is a tasteless product is intended for pediatric usage.

Sar Of Chloramphenicol

Modification of the p-nitrophenyl group:

The para-nitrophenyl group may be modified through the following ways:

1. Replacement of the nitro group by other substituents leads to a reduction in activity.
2. Shifting of the nitro group from the para position also reduces the antibacterial activity.
3. Replacement of the phenyl group by the alicyclic moieties results in less potent compounds.

Modification of dichloro acetamido side chain: Other halo derivatives of the side chain are less potent although major activities are retained.

Modification of 1,3-propanediol: If the primary alcoholic group on the C-l atom is modified, it results in a decrease in activity; hence, the alcoholic group seems to be essential for activity.

Metabolism

Major route: Formation of 3-O-Glucrodination

Minor route: Reduction of the p-Nitro group to amino

Metabolism Use

• Meningitis
• Active against gm+ve and gm-ve bacteria that are resistant to PenicillinG and ampicillin.
• Active against H.Influenza, S.Typhi, S.Pneumonia, B.fragilis and N.meningitis
• In UTI
• Rickettsial infections as “Rocky Mountain Spotted Fever”

Synthesis Of Chloramphenicol

Vancomycin

Vancomycin is an antibiotic that has been around for the last forty years. Recently, however, vancomycin has been increasing in popularity because of its effectiveness in treating resistant organisms. One of two glycopeptide antibiotics in clinical use, vancomycin has a unique chemical structure.

• Vancomycin is comprised of a glycosylated hexapeptide chain containing unusual amino acids. In addition, vancomycin is fairly rigid because of aromatic rings that are halogenated and crosslinked by aryl ether bonds.

Vancomycin can penetrate the gram-positive cell wall and therefore is effective against gram-positive organisms. Vancomycin shows no activity against gram-negative organisms, however, because it is unable to penetrate the gram-negative cell wall.

Vancomycin Mechanism Of Action

• Vancomycin acts by inhibiting bacterial cell wall biosynthesis. Specifically, vancomycin binds to the D-Alanyl-D-Alanine portion of the dipeptide, a key component for the transpeptidase reaction, and forms three hydrogen bonds.
• By covering the substrate for cell wall transaminase, vancomycin prevents the molecule from being transported to the cell wall. Cross-linking does not occur and the integrity of the bacterial cell wall is compromised. The bacterial cell cannot withstand changes in osmotic pressure and it will rupture and die. Vancomycin is bactericidal.

Use Of Vancomycin: Vancomycin is FDA-approved for the treatment of several bacterial infections, including infections caused by susceptible staphylococcus, streptococcus, enterococcus, and diphtheroid organisms. Vancomycin is commonly used in clinical practice to treat endocarditis and meningitis.

Vancomycin Adverse Effects: The most common side effects associated with vancomycin include nausea and vomiting. Rarely, nephrotoxicity, ototoxicity, and neutropenia.

Vancomycin Drug Interactions: Many drugs may increase the adverse effects of vancomycin. Medicines that affect the kidneys, such as aminoglycosides, may increase the risk of kidney damage and should be avoided.

• In addition, co-administration of vancomycin and succinylcholine may result in a prolonged neuromuscular blockade.
• Patients should be monitored and a dose adjustment may be necessary.
• Vancomycin also has been reported to moderately interact with warfarin, potentially increasing the risk of bleeding.
• Patients who take warfarin should be closely monitored as they initiate and stop vancomycin therapy.

Clindamycin

Clindamycin belongs to a class called Lincomycins which were isolated from Streptomyces. This class resembles another antibiotic class called Macrolides and is active against both gram-negative, and gram-positive bacteria, and anaerobes.

Lincomycin

Lmcomycin shows cross-resistance with other Macrolides and Stre’ptoGramins because they bmd to the ribosome m the same way. Lincomycins are water soluble and when given as a HC1 salt they can distribute to other body tissues.

Lincomycin Mechanisam Of Action: The Lincomycins, like the Macrolides, are bacteriostatic. They act by binding to the 50S ribosomal subunit and causing the release of a fragmentary peptide by preventing the translocation of peptidyl-tRNA from the A-site to the P-site. By inducing the formation of these incomplete peptides, the growth of the bacterial cell is inhibited.

Use Of Clindamycin

Clindamycin is FDA-approved for the treatment of bacterial infections due to Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pyogenes, as well as for the treatment of acne vulgaris, bacterial vaginosis, and pelvic inflammatory disease.

Clindamycin Adverse Effects

• The most common adverse effects reported with clindamycin use are diarrhea, nausea, and rash. In rare cases, clindamycin may cause pseudomembranous enterocolitis.
• Clindamycin may also affect the liver, resulting in jaundice and increased liver function tests. Clindamycin is contraindicated in patients with an allergy to clindamycin or lincomycin.

Macrolide Antibiotics Multiple Choice Question And Answers

Question 1. The commercial product of macrolides is…

1. Erythromycin A
2. Erythromycin B
3. Erythromycin C Macrolides act on…
4. Erythromycin D

Answer: 1. Erythromycin A

Question 2. Macrolide acts on.

1. Erythromycin A
2. 30s ribosome
3. Both
4. None

Answer: 1. Erythromycin A

Question 3. Which macrolides contain a 15-membered ring in their structure …

1. Erythromycin
2. Azithromycin
3. Clarithromycin
4. Roxithromycin

Answer: 2. azithromycin

Question 4. Dopamine is a.

1. Acidic ring
2. Basic ring
3. Neutral
4. None

Answer: 2. Basic ring

Question 5. Phototoxicity is the adverse effect of

1. Chlortetracycline
2. rolitetracycline
3. Demeclocycline macrolide acts on
4. doxycycline

Answer: 3. Demeclocycline macrolide acts on

Question 6.Macrolide act on

1. 50s subunit
2. 30s subunit
3. 80s subunit
4. 70s Subunit

Answer: 1. 50s subunit

Question 7. Chloramphenicol act on

1. 50s subunit
2. 30s subunit
3. 80s subunit
4. 70s subunit

Answer: 2.30s subunit

Question 8. Adverse effect of chloramphenicol is

1. Gray baby syndrome
2. Fanconi syndrome
3. Ototoxicity
4. Red man syndrome

Answer: 1. Gray baby syndrome

Question 9. The drug of choice for Rocky Mountain spotted

1. Chloramphenicol
2. Aminoglycosides
3. tetracycline
4. Macrolide

Answer: 1. Chloramphenicol

Question 10. Vancomycin acts on

1. D-Alanyl-D-Alanine
2. L- Alanyi D- Alanyl-D-Alanineboth
3. Both
4. None

Answer: 1. D-Alanyl-D-Alanine

Macrolide Antibiotics Short Question And Answers

Question 1. Classify 14 membered macrolides
Answer:

14 membered macrolides

• Clarithromycin
• Dirithromycin
• Flurithromycin
• Troleandomyci
• Erythromycin
• Roxithromycin

Question .2 Write In mime ketolides.
Answer:

In mime ketolides

• Modithromycin
• Telithromycin
• Cethromycin
• Modithromycin
• Telithromycin
• Solithromycin

Question 3. What In the mode of action of macrolides?
Answer:

The mode of action of macrolides: Bind 509 Hiibunil of ribosome causing them to dissociate from the mRNA resulting in premature termination of the amino acid chain and cessation of protein synthesis.

Question 4 . How does azithromycin degrade?
Answer:

Removal of 9-keto group-increasing stability of azithromycin to acid-catalyzed degradation. These changes also increase lipid solubility.

Question 5. What is the activity spectrum of macrolides?

Answer:

The activity spectrum of macrolides: Active against gm+ve cocci, bacilli, and gm-ve cocci Also active against H.Influenza, mycoplasma pneumonia, N.Gonorrhoea, and legionella

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

Mode of action of macrolide: Bind to 50s subunit of ribosomes causing them to dissociate from the mRNA resulting in premature termination of the amino acid chain & cessation of protein synthesis.

Question 7. Write the mode of action of chloramphenicol.
Answer:

Mode of action of chloramphenicol: Chloramphenicol is a bacteriostatic by inhibiting protein synthesis. It prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome. It specifically binds to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit, ‘preventing peptide bond formation.

Question 8. Write the adverse effect of chloramphenicol.
Answer:

The adverse effect of chloramphenicol: Aplastic anemia is rare Gray baby syndrome in neonates (decreases glucuronysyl transferase) optic neuritis in children.

Question 9. Write the adverse effects of clindamycin.
Answer:

The adverse effects of clindamycin: The most common adverse effects reported with clindamycin use are diarrhea, nausea, and rash. In rare cases, clindamycin may cause pseudomembranous enterocolitis.

Question 10 Write the mode of action of clindamycin.
Answer:

The mode of action of clindamycin: They act by binding to the 50S ribosomal subunit and causing the release of a fragmentary peptide by preventing the translocation of peptidyl-tRNA from the A-site to the P-site. By inducing the formation of these incomplete peptides, the growth of the bacterial cell is inhibited.

Question 11. Write the mode of action of vancomycin.
Answer:

The mode of action of vancomycin: Vancomycin acts by inhibiting bacterial cell wall biosynthesis. Specifically, vancomycin binds to the D-Alanyl-D-Alanine portion of the dipeptide, a key component for the transpeptidase reaction, and forms three hydrogen bonds. By covering the substrate for cell wall transaminase, vancomycin prevents the molecule from being; transported to the cell wall.

Amino Glycosides Introduction

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar).

• The term can also refer more generally to any organic molecule that contains amino-sugar substructures.
• The aminoglycoside antibiotics contain one or more amino sugars linked to an aminocytitol ring by glycosidic bonds.
• Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli were resistant to Gram-positive and anaerobic Gram-negative bacteria. Streptomycin is the first antibiotic of this group.

Aminoglycosides

• Systemic aminoglycosides
• Streptomycin Amikacin
• Gentamicin
• Sisomicin
• Kanamycin
• Netilmicin
• Tobramycin
• Paromomycin

Topical aminoglycosides

• Neomycin
• Framycetin

Amino Glycosides Mode Of Action

The aminoglycosides exhibit bactericidal effects as a result of several phenomena. Klbosomal binding on the 30s and SOs subunits as well as (the interface produces misreading; this is normal protein synthesis, Cell membrane damage also plays an integral part in ensuring bacterial cell death.

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Amino Glycosides Adverse Effect

The aminoglycoside can produce severe adverse effects, which include nephrotoxicity, ototoxicity, and neuro effects.

These properties have limited the use of aminoglycoside chemotherapy to serious systemic indications.

Amino Glycosides Classification

Streptomycin: It is used in the treatment of infections caused by gram-negative bacteria of particular interest and has a high degree of activity against P. aeruginosa, where the important causative factor is burned skin. It is used topically in the treatment of infected bed sores, pyodermata, burns, and eye infections.

Neomycin: It is photosensitive and its main use is in the treatment of ear eye and skin infections This includes burns wounds nuclear and infected dermatoses.

Tobramycin: Its activity is similar to gentamycin. The superior activity of tobramycin against P. aeruginosa may make it useful in the treatment of bacterial osteomyelitis and pneumonia caused by Pseudomonas species.

Sar Of Amino Glycoside

The aminoglycosides consist of two or more amino sugars joined in glycoside linkage to a highly substituted 3 diaminocyclo hexane (amino cyclitol), which is a centrally placed ring.

• The ring is a 2-deoxy streptamine in all aminoglycosides except streptomycin and dihydrostreptomycin, where it is streptidine. Thus,
• In the kanamycin and gentamycin families, two amino sugars are attached to 2-deoxy streptamine.
• In streptomycin, two amino sugars are attached to strepidine.
• In the neomycin family, there are amino sugars attached to 2-deoxy streptamine.

The aminoglycoside antibiotics contain two important structural features. They are amino sugar portions and centrally placed hexose rings, which are either 2-deoxystreptamine or streptidine.

Amino sugar portion

The bacterial inactivating enzymes target C-6 and C-2 position and the substitution with methyl group at C-6 increases the enzyme resistance. Cleavage of 3-hydroxyl or the 4-hydroxyl or both groups does not affect the activity.

Centrally placed hexose ring (aminocyclitol ring): Various modifications at the C-l amino group have been tested.

• The acylation (for example amikacin) and ethylation (for example  1-N-ethylsisomycin) though do not increase the activity help to retain the antibacterial potency.
• In the sisomicin series, 2-hydroxylation and 5-deoxygenation result in the increased inhibition of bacterial inactivating enzyme systems.
• Thus, very few modifications of the central ring are possible, which do not violate the activity spectrum of aminoglycosides.

Amino Glycosides Multiple Choice Questions

Question 1. Which effect is related to aminoglycoside

1. Gray baby syndrome
2. Ototoxicity
3. Fanconi syndrome
4. None

Answer: 2. Ototoxicity

Question 2. Amino glycoside gives.

1. Bactericidal effect
2. Bacteriostatic effect
3. Fungicidal effect
4. None

Answer: 1. Bactericidal effect

Question 3. How aminoglycosides act as …

1. Act on 30s ribosome
2. Framacitin
3. Both 30s and 50s
4. None

Answer: 3. Both 30s and 50s

Question 4. Which aminoglycoside is used as topical?

1. Neomycin
2. Framacitin
3. Both
4. None

Answer: 3. Both

Question 5. Which linkage is found in the aminoglycoside ring and sugar

1. Glycosidic linkage
2. Hydrogen Bonding
3. Covalent Bond
4. All

Answer: 1. Glycosidic linkage

Amino Glycosides Short  Question And Answers

Question 1.  What is the mode of action of aminoglycoside?
Answer:

Mode of action of aminoglycoside: The aminoglycosides exhibit bactericidal effects as a result of several phenomena. Ribosomal binding on 30s and 50s subunits as well as the interface produces misreading; this disturbs the normal protein synthesis.

Question 2. What is the structure of neomycin?
Answer:

Structure of neomycin

 

Question 3. What is the role of the amino cyclitol ring in the SAR of aminoglycoside?
Answer:

Role of the amino cyclitol ring in the SAR of aminoglycoside: Various modifications at the C-l amino group have been tested. The acylation (for example, amikacin) and ethylation (for example 1-N ethylsisomycin) though do not increase the activity help to retain the antibacterial potency.

Question 4. What is the common adverse effect of aminoglycoside?
Answer:

Common adverse effects of aminoglycoside: The aminoglycoside can produce severe adverse effects, which include nephrotoxicity, ototoxicity, and neuro effects. These properties have limited the use of aminoglycoside chemotherapy to serious systemic indications

Question 5. What are aminoglycosides?
Answer:

Aminoglycosides: Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar).

• The term can also refer more generally to any organic molecule that contains amino-sugar substructures.
• The aminoglycoside antibiotics contain one or more amino sugars linked to an aminocytitol ring by glycosidic bonds.

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.