Dr. Subhash Technical Campus
Faculty of Pharmacy ======
Study material
Subject: Medicinal Chemistry – III
Subject Code: BP601TP
Prepared by: Prof. B. B. Vaghasia
Dr. Subhash Technical Campus
Faculty of Pharmacy ======List of important questions
1. Classify penicillins with structure. Explain degradation product of penicillins. 2. Explain Chemistry and SAR of Penicillins. 3. Enlist different beta lactam antibiotics. Explain MOA of beta lactam antibiotics. 4. Classify cephalosporins with structure. Explain SAR of cephalosporins. 5. Write a note on aminoglycosides antibiotics. 6. Write a note on macrolide antibiotics. 7. Write about SAR and MOA of tetracycline antibiotics. 8. Explain SAR and synthesis of Chloramphenicol. 9. Define prodrug. Write about application of prodrug design. 10. Write a note on beta lactamase inhibitors and monobactams. 11. Enlist different disease caused by Protozoa. Explain life cycle of malarial parasite. 12. Define antimalarial agents. Classify them with structures. 13. Explain SAR of Quinolines antimalarial drugs. 14. Write synthesis and uses of Chloroquine and Pamaquine. 15. Define anti TB drugs. Explain first line treatment for TB. 16. Classify anti TB drugs. Explain second line treatment for TB. 17. Classify Quinolones. Explain mechanism of action of Quinolones. 18. Explain SAR of Quinolones and write a synthesis of Ciprofloxacin. 19. Explain SAR and MOA of Sulfonamides. 20. Write synthesis and uses of Sulfacetamide and Sulfamethoxazole. 21. Define Antifungal drugs and explain antifungal antibiotics. 22. Classify Antifungal drugs and explain azoles antifungal. 23. Write synthesis and uses of Miconazole and Tolnaftate. 24. What is amoebiasis. Write a note on antiamoebic agents. 25. Write a note on anthelmintic drugs. 26. Write synthesis and uses of Metronidazole and Mebendazole. 27. Define and classify antiviral agents. Explain purine nucleosides and nucleotides. 28. What is QSAR? Give a detailed note on Hansch model. Dr. Subhash Technical Campus
Faculty of Pharmacy ======29. Write a note on Hammett substitution constant (electronic parameter) used in QSAR studies. 30. Write a detailed note on Combinatorial Chemistry. 31. Classify anti HIV drugs. Write a note on reverse transcriptase inhibitors. Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q.-1 Classify penicillins with structure. Explain degradation product of penicillins.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q-2. Explain Chemistry and SAR of Penicillins. ➢ Long after the antibiotic projected its appearance on screen of research, the structure of penicillin was determined. ➢ The penicillins can be considered as the amido derivatives of the 6-amino penicillanic acid.
➢ In the basic skeleton, a thiazolidine ring (A) is fused with a beta lactam ring (B) which is a 4- membered cyclic amide. ➢ The penicillins differ from each other in antibacterial and pharmacological characteristics due to variation in the structure of acid moiety of the amide side chain at C-6.
For example- Penicillin G (where R=C6H5CH2-, benzyl group). It is natural penicillin which used about 45 years and the only natural penicillin used clinically. ➢ Acylation of 6 – APA with appropriate carboxylic acids resulted in new penicillins, some of which are broad spectrum antibiotics. ➢ The side chain of natural penicillin can be split off by an amidase to produce 6 – APA.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q - 3. Enlist different beta lactam antibiotics. Explain MOA of beta lactam antibiotics. ➢ The beta lactam antibiotics are as follows • Penicillins • Cephalosporins • Carbapenams • Monobactams Mechanism of action: ➢ All β-lactam antibiotic interfere with synthesis of cell wall. ➢ The bacteria synthesize UDP-N-acetylmuramic acid pentapeptide, called Park nucleotide and UDP – acetylglucosamine. ➢ The peptidoglycan residues are linked together forming long strands and UDP is split off. ➢ The final step is cleavage of the terminal alanine of the peptide chains by transpeptidases, the energy so released is utilized for establishment of cross linkage between peptide chain of the neighbouring strands. ➢ This cross-linking provides stability and rigidity to the cell wall.(mucopeptide synthesis) ➢ The beta-lactam antibiotic inhibit transpeptidase so that cross linking(which maintain the close knit structure of the cell wall) does not take place. ➢ These enzyme and related proteins probabally constitute penicillin binding protein which have been located in the bacterial cell membrane.
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Medicinal chemistry- III (BP601TP)
Q-4. Classify cephalosporins with structure. Explain SAR of cephalosporin.
➢ The cephalosporins are β-lactam antibiotics isolated from cephalosporium species or prepared semisynthetically. ➢ They can be classified as follows: 1) First generation cephalosporins: highly active against gram positive and lowest active against gram negative bacteria. Example: Cephaloridine, Cephazolin, Cephalexin, Cefadroxil etc.
2) Second generation cephalosporins: more active against negative enteric bacteria. Example: Cefoxitin, Cefuroxime, Cefactor etc.
3) Third generation cephalosporins: broader antibacterial activity. Example: Ceftizoxime, Cefotaxime, Ceftriaxone etc.
4) Forth generation cephalosporins: Broad spectrum antibacterial agents. Example: Cefepime, Cefepirome
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Medicinal chemistry- III (BP601TP)
Structure activity relationship (SAR): ➢ Cephalosporin C, natural product itself was unsuitable as a clinical antibiotic. ➢ The structure would have to be modified in the laboratory to give a more potent semisynthetic analog. ➢ The semisynthetic cephalosporins obtained by attaching a side chain to 7- amino cephalosporinic acid. ➢ Virtually all position of the cephalosporin residues have been varied as illustrated in figure: (1) The cephalosporins are considered as broad spectrum antibiotics with patterns of antibacterial effectiveness similar to ampicillins.
(2) 7 – acylamino substitution: a) Simply acylation of the amino group generally result in an increase in gram positive activity but it is accompanied by decrease in gram positive potency. b) Substitution on the aromatic ring phenyl (when present) that increase lipophilicity provide higher gram positive activity and generally lower gram negative activity. c) Similar to penicillin series, phenylglycine moiety if attached to 7 – amino cephalosporanic acid affords a compound with increased oral activity. Example – Cephaloglycin. d) The phenyl ring in the side chain can be replaced with other heterocyclic with improved spectrum of activity and pharmacokinetic properties. Example – Thiophene in cephalothin Tetrazole in cefazolin Furan in cefuroxime e) The aminothiazole group improves gram negative activity; Ex – cefotaxime. f) The presence of catechol grouping can also enhance activity particularly against pseudomonas aeruginosa. g) Acylation of the amino group of 2- phenylglycine containing cephalosporins (eg.- Cephaloglycin) is consistent with anti pseudomonal activity; eg.-cefoparazone.
(3) Modification involving 3-substituent:
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a) However allylic acetoxy group at C-3 is apparently not necessary for antibiotic activity (eg. – Cephalexin, cephradine do not contain this group) but its position C-3 is important for pharmacokinetic and some time pharmacological and antibacterial property. b) Pyridine (cephaloridin) and imidazole replaced acetoxy group shows extended activity for gram negative and pseudomonas aeruginosa. c) Displacement with sulfur nucleophiles (aromatic thiols) of 3 – acetoxy group results in enhanced intrinsic acivity especially against gram –ve bacteria.
(4) Substitution at 7 position: a) The 7β amino group is essential for antimicrobial activity, wherase replacement of the hydrogen at C-7 (X=H) with an alkoxy (X=OR) results in improvement of the antibacterial activity of the cephalosporin. b) Within specific cephalosporin derivative, the addition of 7-α methoxy also improves the drug stability towards β-lactamase. eg. – cefoxitin.
(5) Modification of 2 – COOH group: a) The carboxy group of position 2 has been converted into ester prodrug to increase the bioavailability of cephalosporin and these can be given orally as well. (6) Olefinic linkage at C2-3 is essential for antibacterial activity. Isomerisation of the double bond to 3-4 position leads to great losses in antibiotic activity. (7) The derivative where position 5 has sulphur exhibit antibacterial activity than if it is oxygen and other.
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Medicinal chemistry- III (BP601TP)
Q-5. Write a note on aminoglycosides antibiotics.
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Medicinal chemistry- III (BP601TP)
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Medicinal chemistry- III (BP601TP)
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Medicinal chemistry- III (BP601TP)
Q - 6. Write a note on macrolide antibiotics. ➢ The term macrolides is derived from the characteristic large lactone (cyclic ester) ring found in these antibiotics e.g. erythromycin, clarithromycin, azithromycin Structure and chemistry: ➢ Macrolide antibiotics are produced by streptomyces species. They are characterized by some following common chemical features. ➢ A large lactone ring usually having 12,14,15 or 16 atom in it hence the name macrolide. ➢ A ketone group ➢ A glycosidically linked aminosugar ➢ Lactone ring is often unsaturated with an olifinic group conjugated with the ketone function. ➢ The clinically important members of antibiotic family have two or more characteristic sugar (usually cladinose and dexosamine) attached to large lactone ribg. ➢ One of the sugars usually carries a substitute amino group so that overall characteristic weakly basic. Chemical properties: ➢ The free bases are only slightly soluble in water dissolve in somewhat polar organic solvent. ➢ They are stable in aqueous solution at or below room temperature but are inactivated by acid, bases and heat. ➢ These are chemically unstable because of rapid acid hydrolysis (GIT tract) most acid susceptible macrolides are administered in coated tablets to minimize effect. ➢ Semisynthetic derivative have been prepared that are structurally incapable of undergoing this reaction. ➢ Many macrolides have an unpleasant taste, which is partially overcome with water-insoluble dosage forms that also reduce acid instability and gut cramps. Structure activity relationship (SAR): ➢ As we know structure of macrolides contain 3 important including- 1. A lactone ring/cyclic ether(ester) 2. A glycosidically linked amino sugar. 3. Normal sugar(simple lactone) ➢ All those structural moieties are essential for activity however various modifications were reported that affect or influence pharmacodynamic as well as pharmacokinetic of the drugs these are-
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(I) Modification related to lactone ring (large) ➢ For maximum activity generally lactone ring have 12,14,15 or 16 atoms. Example- Erythromycin which contains lactone ring having 14 atoms Azithromycin which contain large lactone ring having 15 atoms ➢ C-12 hydroxy group in erythromycin family influence stability as well as activity if the drug, ex.- • Erythromycin B which does not contain C-12-OH more stable but less active.(since –OH is responsible for enzymatic degredation) • Erythromycin A which contain C-12-OH more active less stable. ➢ C-6 hydroxy group- methylation of C-OH group of erythromycin n creates semisynthetic derivative. ➢ Clarithromycin cause- • Retention in activity • Increase oral bioavailability • Increase acid stability • Reduce GIT irritation
➢ Removal of 9-keto group coupled with incorporation of a weakly basic tertiary amine nitrogen function into the macrolide ring cause- • Increase in stability to acid catalysed degredation • Increase lipid solubility of molecule confirming unique pharmacokinetics. Example- Azithromycin.
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➢ Introduction of amino nitrogen at atom 9 and formation of 9N-110-oxazine ring thus formed is heminal-cause • Inhance lipophilicity, rapid distribution • But less stable under acidic and alkaline medium. • Example- dirithromycin ➢ A14-membered lactone ring possessing exocyclic methylene epoxide onC-8 which is also active. E.g- oleandomycin (II) Modification related to aminosugar ➢ Due to presence of amino sugar (amino group) overall characteristic is weakly basic. ➢ The basic nature of the dimethylamino group of dexosamine moiety was utilized to prepare its acid salts, like the lactobionate, glucoheptonate and stearate ➢ Increase stability ➢ Better activity. ➢ Ester of hydroxy group of dexosamine including the ethyl carbonate, ethyl succinate and estolate ➢ Example- erythromycin estolate more stable promote high oral absorption (Prodrug) (III) Modification related to simple sugar ➢ Cladinose sugar is not necessary for activity. It may be other cyclic ether ➢ Oleandomycin contain L-oleandorose as compare to cladinose.
➢ A triacetyl ester derivative a more preferred form of oleandomycin is prepared by acetylating 3- OH group one in each of sugar’s and one in the oleandomycin (large lactone) results- ➢ Retention of invivo antibiotic activity ➢ Superior pharmacokinetic properties(increase lipophilicity) ➢ Its tasteless in nature Antimicrobial spectrum
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➢ It is narrow spectrum, includes mostly gram positive and few gram negative organisms and overlaps considerably with that of penicillin G, erythromycin is highly active against step.pyrogenes and strep. Pneumonia, n. gonnorrhoea, clostridia, c.deptheriae and listeria ➢ Most penicillin resistance staphylococci and streptococci were initially sensitive but have now become resistant to erythromycin also. ➢ In addition campylobacter legionella, branhamella, catarrhalis, gardnerella, vaginallin and mycoplasma are highly sensitive. Mechanism of action ➢ Erythromycin is baccteriostatic at low but cidal at high concentrations. ➢ Cidal action is also depend on the organism concerned and its rate of multiplication . ➢ Sensitive gram positive bacteria accumulate erythromycin intracellularly by active transport mechanism. ➢ It is several fold more active in alkaline medium because the non-ionized(penetrable)form of drug is favourd at higher pH. ➢ Erythromycin acts by inhibiting bacterial protein synthesis ➢ It combines with SOS ribosome subunit and interfers with translocation after peptide bond formation between the newly attached amino acid and the nacent peptide chain at the accepter A site the elongated peptide is translocated back to the peptidyl P site , making the A site available for next amino acyl tRNA attachment. ➢ This is prevented by erythromycin and the ribosome fails to more along the mRNA to expose the next codon. ➢ Synthesis of larger proteins are specially suppressed. Adverse effects ➢ Epigastric distress ➢ Cholestatic jaundice ➢ Ototoxicity ➢ Contraindicated with hepatic dysfunction patients due to accumulation of drug in liver ➢ Interaction: due to inhibition of hepatic metabolism of some drug(digoxin)
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Medicinal chemistry- III (BP601TP)
Q-7. Write about SAR and MOA of tetracycline antibiotics. ➢ Tetracyclines are most important broad spectrum antibiotics. Structure activity relationship:
Modification of C1 and C3 position: • The keto-enol system between carbon atom 1 and 3 is highly delocalized extremely slow to react. • This keto-enol toutomerism of ring A is a feature common to all biological active TCS. • Blocking this system by forming derivative at C1 and C3 result inn loss of antibacterial activity.
Modification of C2 protein: • The amide carbonyl appears to be essential for TC activity but not the amide nitrogen mannich amino alkylation of the amide group gives rise to derivative which are freely water soluble in the physiological pH range which hydrolyze slowly in vivo and in vivo and posses the same spectrum of activity as starting marerial. Modification with C4 position: • It has been shown that an equilibrium between the non ionized and zwitter ionic structure is necessary for the antibacterial activity. • The dimethyl amino group in the 4 position is essential for maintaining invivo and invitro activity because lack of the dimethylamino group presents the formation of the zwitter ion which is essential for optimum distribution. Modification of the C5 and C5a position: • 5 position does not appear to be particularly crucial to tetracycline. • The stereochemistry at the C5a position is the alpha configuration. Modification of the C6 position: • The hydroxy group at C6 makes the molecule unstable to both acids and bases,
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• Elimination of the 6-OH group produces tetracyclines which are both more lipophillic and more stable to acids. e.g : doxycycline is absorbed more • In general C6 methylated analogs achieve higher blood levels. • 6-thiatetracyclines in a preliminary report one showing excellent superior pattern of activity. They contain a sulphur atom at C-6. • Arecent derivative thiacycline is found to be more active than minocycline against tetracycline resistant bacteria. • The introduction of larger substituent at C6 causes the compounds to be more lipophillic and thus lessens their activity against gram-negative organisms. Modification of the C7 position: • C-7 substitution results in increased potency and the drug may sometimes be active against resistant microbial strain. • Electron withdrawing group and electron donating group both are equally effective at C-7 e.g: chlortetracycline contains an electron withdrawing group at C7 and minocyclines posses an electron releasing (dimethylamino group) at C-7 position. • The SAR of position 5,6,7,and 9 can be modified by various substituents resulting into retention and in some cases improvement of antibiotic activity. • A cis tape fusion between A/B with an alpha hydroxy group at 12a is necessary for retention of activity. • Semisynthetic analogs have also been obtained in an attempt to achieve advance in chemotherapy. Methacycline,doxycline and minocycline are some results of such efforts. Mechanism of action: • The strong binding properties of the tetracycline with metal ions caused to suggest that their antibacterial properties may be due to qan ability to remove essential metal ions as chelated compounds. • Tetracyclines are specific inhibitors of bacterial protein synthesis. • They bind to the 30s ribosomal subunit and thereby present the binding of aminoacyl tRNA to the mRNA ribosomal complex. • Both the binding of aminoacyl tRNA and the binding of tetracyclins at the ribosomal binding site require magnesium ions. • Tetracyclines also bind to mammalian ribosomes but with lower affinities and they apparently do not achieve sufficient intracellular concentrations to interfere with protein synthesis. • The selective toxicity of the tetracyclins towards bacteria depends strongly on the self destructive capacity of bacterial cells to concentrate these agents in the cell.
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Medicinal chemistry- III (BP601TP)
• Tetracyclines enter bacterial cells by two process: passive diffusion and active transport. • The active uptake of tetracyclines by bacterial cells is an energy-dependent process that requires adenosine triphosphate(ATP) and mangnesium ions.
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Medicinal chemistry- III (BP601TP)
Q-8. Explain SAR and synthesis of Chloramphenicol. • Chloramphenicol is a levorotatory broad sprctrum antibiotic. Structure activity relationship: • SAR of chloramphenicol can be studied under the following headings:
• It consists of three important parts 1. P-nitrophenyl group 2. Dichloroacetamido side chain 3. 1,3-propandiol. (1) SAR of P-nitrophenyl group • Replacements of the nitro group by other substituents leads to reduction of activity. • Shifting of the nitro group from para position also reduce the antibacterial activity. • Replacement of phenyl group by the alicyclic moieties results in less potent compounds • The p-nitrophenyl group may be replaced by other aryl structures without appreciable loss of activity. (2) SAR of Dichloroactanido side chain: • Other dihalo derivatives of the side chain are less potent though major activities are retained • While in case of trihalo derivatives , Hansen by the Qsar calculation claimed that
2NHCOCF3 derivative would be about 1,7 times as active as the chloramphenicol. (3) SAR of 1,3- propanediol: • Alcoholic group on C1 atom if modified, results in decrease in activity hence the alcoholic groups seems to be essential for activity. • Conversion of the alcoholic group on C1 of the side chain to a keto group causeappreciable loss in activity.
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Medicinal chemistry- III (BP601TP)
• Chrloramphenicol posses two chiral (asymmetric) carbon atoms in the acylaminopropanediol chain:
• Thus there are two possible pair of enantiomorphs. • It has been observed that the biological activity resides almost exclusively in the D- threo-isomer whereas the L-threo and D-and L-erythro isomers are virtually inactive.
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Synthesis of Chloramphenicol:
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Q-9. Define prodrug. Write about application of prodrug design. Prodrug: It is chemically modified inert drug precursor, which upon biotranfformation liberates the pharmacologically active parent compound. Application of Prodrug: Pharmaceutical Application: Masking taste or odour: • Undesirable taste arise due to adequate solubility and interaction waste receptors. • It can be solved by lowering the solubility of the drug or prodrug in saliva. e.g: chloramphenicol palmitate is the sparingly soluble of prodrug of chloramphenicol, which is practically tasteless due to its low aqueous solubility, as well as it is hydrolysed to active chloramphenicol by the action of pancreatic lipase.
e.g: Ethyl mercaptan has a boiling point of 250C and a strong disagreeable odour. But diethyldithioisopthalate, prodrug of ethyl mercaptan has a higher boiling point and is relatively odourless. Reduction of gastric irritation: E.g: aspirin is a prodrug of salicylic acid is designed to reduce gastric irritation
Reduction in pain at site of injection: • Pain caused by intracellular injection is mainly due to the weakly acidic nature or poor aqueous solubility of drugs E.g: IM injection of antibiotic like clindamycin and anti convulsant like phenytoin was found to be painful due to poor solubility. So prodrug are produced like 2-phosphate ester of clindamycin and hydantoic ester prodrug of phenytoin(fosphenytoin) an aqueous soluble form of phenytoin respectively.
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Medicinal chemistry- III (BP601TP)
Enhancement of drug solubility and dissolution rate: • The prodrug approach can be used to increase or decrease the solubility of a drug depending on its ultimate use. E.g: chloramphenicol succinate and chloramphenicol palmitate, ester prodrugs of chloramphenicol, have enhanced and reduced aqueous solubility respectively. On the basis of altered solubility, chloramphenicol sodium succinate prodrug is found suitable for parenteral administration. • The prodrug approach is also made useful for better gastrointestinal absorption. E.g: sulindac, a prodrug of sulindac sulfide being more water soluble with sufficient lipophilicity makes this drug suitable for oral administration. ✓ Testosterone- testosterone phosphate ester ✓ Tetracycline- tetralysine ✓ Diazepam-diazepam L-lysine ester.
Enhancement of chemical stability: • Chemical stability is an utmost necessary parameter for every therapeutic agent. • The prodrug approach is based on the modification of the functional group responsible for the instability or by changing the physical properties of the drug resulting in the reduction of contact between the drug and the medi in which it is unstable. E.g: antineoplastic drug Azacytidine in aqueous is readily hydrolyzed but its bisulphate prodrug is stable.
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Medicinal chemistry- III (BP601TP)
E.g: inhibiting the auto aminolysis, which occur due to capability of side chain to attach Beta lactam ring of other molecule, in ampicillin molecule in concentrated solution it generates polymeric species of ampicillin by making hetacillin, a prodrug of ampicillin formed by the reaction of acetone and ampicillin ties up the amine group and thus inhibite auto aminolysis.
Pharmakokinetic Application: Improvement of Bio availability: Enhanccement of oral Bio availability: • Various therapeutic agents such as water soluble vitamins, structuralanalogues of natural purine and pyrimidine nucleoside , dopamine antibiotics like ampicillin and carbenicillin, phenytoin and cardiac glycoside such as gitoxin suffers with poor gastrointestinal absorption. • The prime cause of the poor absorption of these agents is their likely polar nature ,poor lipophilicity and /or metabolism during absorption process. • On contrary gitoxin, a cardiac glycoside has very poor oral bioavailability due to limited aqueous solubility. • Absorption of water soluble vitamins was enhanced by derivatization of thiolate ion to form lipid soluble prodrugs. • Dopamine was made useful by making its precursor L-dopa. Though L-dopa is highly polar, it is actively transported through specific L-aminoacid active transport mechanism and regenerates dopamine by decarboxylation.
• Penta acetyl prodrug of gitoxin has four to five times more aqueous solubility. • To increase aqueous solubility esterification with amino acids is done. • Examples of such prodrugs are valacyclovir and valgancyclovir which are valine esters of the antiviral drugs acyclovir and gancyclovir, respectively. Enhancement of ophthalmic bioavailability:
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Medicinal chemistry- III (BP601TP)
• Epinephrine –dipivalyl derivative latanoprast and travoprast-isopropyl esters of latanoprast acid and travoprost acid Enhancement of percutaneous bioavilability: • Mefenide-mefenide hydrochloride/acetate Enhancement of topical administration: • Ketolac-esters of ketolac Prevention of presystematic metabolism: • For oral administration , a drug must pass through two metabolizing organs i.e liver and gastrointestinal mucosa, before reaching the general circulation. • Phenolic moiety, oxidative N- and O- dealkyaltion ester cleavage and peptide degredation are responsible for the pre systematic metabolism of various frugs..two types of drugs fall into this category. 1. The first are drugs rapidly degraded by the acid condition of the stomach. 2. Drugs of second category degrade due to enzymes present in the GIT mucosa and liver. • Prodrug may protect a drug from presystematic metabolism. • Naltrexone (treatment of opioid addiction) and is readily absorbed from GIT and hence undergoes presystematic metabolism. • Ester prodrugs such ass O-nitro benzoate, heroin and acetylsalicylate increased bioavailability 45 and 28 fold respectively
Prolongation of duration of action: • Drugs with short half life require frequent dosing with conventional dosage forms to maintain adequate plasma concentration of the particular drug. • In plasma level time profile and consequently patient compliance os often poor. • Prolongation of duration of action of a drug can be accomplished by the prodrug • Prodrug can be formed by two approaches: 1. Control the release of the drug from complex 2. Control the conversion or prodrug into the parent drug. 3. e.g: nordazepam is an anxiolytic drug; it loses its activity too quickly due to metabolism and excertion. A prodrug introduced to improve the duration of action, due to presence of N- methyl group to resist the quick degradation.
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Site specific drug delivery: • After its absorption into the systematic circulation the drug is distributed to the various parts of the body including the target site as well as the non target issue. • These problems can be overcome by targeting the drug specifically to its site of action by prodrug design. • The prodrug is converted into its active from only in the target organ/tissue by utilizing either specific enzymes or a pH value different from the normal pH for activation E.g: 5-amino salicylic acid • Tumour cells contains a higher concentration of phosphates and amidases than do normal cells • Consequently a prodrug of cytotoxic agent could be directed to tumour cells if either of these enzymes was important to prodrug activation process. • Diethylstilbesterol diphosphate was designed for site specific delivery of diethylstilbesterol to prostatic carcinoma tissue.
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Medicinal chemistry- III (BP601TP)
Q-10. Write a note on beta lactamase inhibitors and monobactams. Beta lactamase inhibitors: • These are chemical moieties which are enable to interact with enzyme beta lactamse produced by many gram positive and gram negative bacteria. T]hese agents cause potent and progressive inactivation of beta lactamse enzyme. • Beta lactamase enzyme inactivate beta lactam antibiotic by opening the beta lactam ring (amide bond).
Importance of beta lactamase inhibitors: • Some of bacterial strain (gram +ve as well as gram -ve) produce a specific type of enzyme which inactivate beta lactam antibiotics called beta lactamase enzymes. • Due to this enzyme inactivation, concentration of active drug decreased. • Betalactamase enzymes can present extracellulary or intracellularly. • Some of bacterial strain also get resist due to its ability to produce these enzyme in excess amount. • beta lactamase inhibitors specifically bind and inactivate these enzymes and protect the drugs actual beta lactam drugs thus helps to maintain the effective concentratin of drugs to be act as bacteriostatic or cidal. • Thus it is helpful or beneficial to administer beta lactam antibiotics along with these beta lactamase inhibitors. Common mechanism of action: • Beta lactamse inhibitors are mostly structural analogues of beta lactam antibiotics.(they contain beta lactam ring ) and having high affinity towards beta lactamse . • It acts as a false substrate for enzyme and inhibit its action or interaction with beta lactam antibiotics (drug)
Classification of beta lactamase inhibitors: • We can classify beta lactamase inhibitors into two classes:
Class -1 drugs: • Have a hetero atom leaving group at position 1 Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 1
Medicinal chemistry- III (BP601TP)
• It is particularly useful in combination • It is very weak antibacterial agent e.g: clavulanic acid , sulbactam and tazobactam. Class -2 drugs: • Does not contain heteroatom leaving group at position -1 • These are potent antibacterial agents. e.g: carbapenam derivative –imipenam some of important drugs are- 1. Clavulanic acid: • It is obtained from streptomyces clauligerus, it has only weak intrinsic antibacterial activity, but it is excellent irreversible inhibitors of most of beta lactamses.
• It is believed to acylate the acive site renine ny mimicking the normal substrate. • Hydrolysis occurs with some beta lactamases, but in many cases subsequent reaction occurs that inhibit the enzymes irreversibly. • This lead to its classification as mechanism based inhibitors.(or so called suicide substrate) • The precise chemistry is not well understood,but when clavulanic acid is added to ampicillin and amoxicillin preparation the potency against beta lactamase producing strain is markedly enhanced. 2. Sulbactam: • It is another beta lactamase disabling agent. • Sulbactam is prepared by partial chemical synthesis from penicillins. • The oxidation of sulphur atom to sulfone greatly enhance the potency of sulbactam.
• Structurally similar to penicillin and also contain beta lactam ring. • The combination of sulbactam and ampicillin is now clinically popular.
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• Clavulanic acid and sulbactam like beta lactamse inhibitors are not effective in case of resistance caused due to change in drug penetration. 3. Tazobactam • Tazobactam is penicillinic acid sulfone that is similar in structure of sulbactam • It is more potent beta lactamase inhibitor than sulbactam and has slight broader spectrum of activity than clavulanic acid. It has very weak antibacterial activity.
• It is mainly used in form of piperacillin –tazobactam combination for various beta lactamase producing strains causing various disease such as appendicitis, post-partum endometrisi etc. Monobactams: • Monobactams are monocyclic and bacterially produced beta lactam antibiotics. • The beta lactam ring is not fused to another ring, in in contrast to most other beta lactams. • They are effective only against aerobic gram negative bacteria (eg. Neisseria, Pseudomonas). • Examples are Aztreonam, Sulfazecin and Tigemonam etc. Aztreonam:
• It is a commercially available monobactam antibiotic. • It is similar in action to penicillin. • It inhibits synthesis of the bacterial cell wall, by blocking peptidoglycan crosslinking. • It binds to penicillin binding proteins bacteria. • It is used primarily to treat infections caused by gram negative bacteria such Pseudomonas aeruginosa.
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Q - 11. Enlist different disease caused by Protozoa. Explain life cycle of malarial parasite.
➢ Different diseases caused by protozoal infection are as below:
1) Amebiasis caused by Entamoeba histolytica
2) Giardiasis caused by Giardia lamblia
3) Trichomoniasis caused by Trichomonas vaginalis
4) Pneumocystis caused by Pneumocystis carinii
5) Trypanosomiasis caused by Trypanosoma cruzi, brucei
6) Leishmaniasis caused by Leishmania Spp.
7) Malaria caused by Plasmodium Spp.
❖ Life cycle of malarial parasite:
➢ Malaria in human caused by the infection with protozoan parasites of the genus, Plasmodium.
➢ These parasites spend an asexual phase in man and a sexual phase in female Anopheles mosquitos.
➢ Out of several hundred species, four species infect man. These includes,
(1) Plasmodium falsiparum
(2) Plasmodium vivax
(3) Plasmodium malariae
(4) Plasmodium ovale
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Q – 12. Define antimalarial agents. Classify them with structures. ❖ Antimalarial agents: ➢ These are drugs used for prophylaxis, treatment and prevention of relapses of malaria.
❖ Classification: ➢ The antimalarial drugs can be classified on the chemical basis. (1) Quinolines a) Cinchona alkaloids: Quinine, Quinidine, Cinchonine, Chinonidine
b) 4 – Amino quinolines: Chloroquine, Amodiaquine
c) 8 – Amino quinolines: Primaquine, Pamaquine
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d) Quinoline methanol: Mefloquine
(2) 9 – Amino acridine: Quinacrine, Acriquine
(3) 2,4 – Diamino pyrimidines: Pyrimethamine, Trimethoprime
(4) Biguanides and dihydrotriazines: Proguanil, Cycloguanil
(5) Sulfonamides & Sulfone: Sulfadiazine, Dapsone
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(6) Sesquiterpine lactones: Artesunate, Artemether.
(7) Naphthoquinones: Atovoquone
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Q – 13. Explain SAR of Quinolines antimalarial drugs. • SAR of quinoline is explained below in its three category. A. cinchona alkaloids:
• Asymmetric at position 3 and 4 is not essential antimalerial activity. • For antimalerial activity, the distance between the oxygen and the non aromatic nitrogen should be about 3A0. • The presence of methoxy group in quinine is not essential. Replacement of methoxy group by a halogen, especially chlorine, enhances activity. • A further increase in activity resulted from the introduction of a phenyl group at position 2. In general blocking of position 2 of the quinoline ring with a phenyl group but not with an aliphatic hydrocarbon led to highly active compounds. • Modification of the secondary alcohol at C-9 through oxidation esterification diminishes activity. • Activity is usually enhanced by the introduction of a halogen at position 8.
B. 4- Amino quinolines:
1. SAR related to quinoline nucleus: • The 7-chloro group in the quinoline nucleus is optimal and methyl group in position 3 reduce activity and an additional methyl group in position 8 completely abolishes the activity. • The quinoline ring system seems to be inherenlt more active than the acridine for a given side chain.
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2. SAR related to side chain: • A dialkylaminoalkyl side chain, having 2-4 carbon atoms between the nitrogen atoms, particularly 4-diethylamino 1- methylbutyl amino side chain is optimal for activity as in chloroquine and quinacrine. • The introduction of an unsaturated bond in the side chain was not affect the activity. • Incorporation of an aromatic ring in the side chain. E.g in amodiaquine gives a compound with red need toxicity and activity. • The D-isomer of chloroquine is some what less toxic than its L-isomer. 3. SAR related to N atom: • The tertiary amine in the side chain is important • The substitution of hydroxyl on one of the ethyl groups on the tertiary amine c hydroxyl quinolines generally reduce toxicity and increase the plasma concentration. This is one of the metabolite of chloroquine.
C. 8-Aminoquinoolines:
• Compound with high therapeutic index had a 6-methoxy group in quinoline nucleus and it may be substituted by H, OH or low OR groups. • The 2, 4, 6-methoxy analogs of 8-diethylamino propylaminoquinoline were all active. The introduction of a second methoxy group at position 2 or 5 increased the therapeutic index. • The extent of substitution of the terminal amine is not as critical as in 4-aminoquinolines, and the terminal aliphatic amino group may be primary, secondary or tertiary. Primaquine is drug of choice is a primary amine but aromatic amine must be secondary. • Additional substituents in the quinoline nucleus at the 4- and 5- position may be beneficial such as 5-phenoxy derivatives.
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Q – 14. Write synthesis and uses of Chloroquine and Pamaquine.
Uses: ➢ Chloroquine is highly effective against the asexual erythrocytic forms of P. vivax and sensitive strains of P. falsiparum and gametocytes of P. vivax. ➢ The completely cures falsiparum malaria. ➢ The major metabolite, monodesethyl chloroquine has also antimalarial activity. ➢ For the treatment of chloroquine resistant falsiparum malaria, a combination therapy comprising of quinine, pyrimethamine and sulfadiazine may be given. ➢ Chloroquine also has anti histaminic and anti inflammatory properties. It is used to treat hepatic amoebiasis, rheumatoid arthritis, discoid lupus erythematous, cutanea tarda, solar urticaria and light eruptions.
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Uses: ➢ It is used for the treatment of malaria and it is closely related to primaquine.
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Q – 15. Define anti TB drugs. Explain first line treatment for TB. ❖ Anti TB drugs: ➢ The anti tubercular drugs are agent used for the treatment of parasitic disease, tuberculosis (TB). ❖ First line agents for treatment of TB: ➢ These drugs have high antitubercular efficacy as well as low toxicity. ➢ Examples of first line agents are as follow: Isoniazid:
➢ This drug was introduced in 1952. It is extremely effective and safe antimycobacterial agent. Chemically it is hydrazide of isonicotinic acid. It exhibit bacteriostatic action on the resting bacilli but bacteriocidal for rapidly develop or dividing micro organisms. ➢ It is colourless, odourless with sweet to bitter taste, soluble in water. ➢ It is an orally active agent and its oral absorption is reduced by the presence of food and antacids. ➢ It does not bind to plasma protein. ➢ It is well distributed to different body tissues and fluids including cerebrospinal fluid because of its wide spread distribution in the body. It is equally effective against all types of tuberculosis. Synthesis:
4 – methyl pyridine Pyridine- 4 – carboxylic acid Isoniazid
Mechanism of action: ➢ Isoniazid inhibits mycolase synthatase, an enzyme necessary for the biosynthesis of mycolic acid. The latter are the important constituents of mycobacterial cell wall.since mycolic acid are present only in mycobacterial action. ➢ Because of its ability to complex essential metals such as copper or iron present in mycobacterial enzyme. ➢ It interfere with various enzyme system requiring pyridoxal phosphate as a cofactor.
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➢ This result in the change in the metabolism of lipid , proteins and carbohydrate. Nucleic acid synthesis is also affected. Adverse effect: ➢ Since the most of isoniazid undergoes metabolism by N-acetylation process in the liver. ➢ The latter depends on the transfer of acetyl group from coenzyme A b y an N-acetly-transferase, the slow acetylation are more susceptible to the adverse effect than rapid acetylators. ➢ Dryness of mouth, epigastric stress, allergic reactions, peripheral neuritis, mental abnormalities, hepatotoxicity. Rifampicin:
➢ It is a semisynthetic derivative of rifampicin-b produced by streptomyces mediterranes. ➢ It is obtained by reacting 3-formylrifampicin Sv with 1-amino-4-methyl piperazine in tetrahydrofuran. ➢ Rifampicin is bactericidal to M. tuberculosis and many other gram positive nad gram negative like stap. Aureus, N.meningitis, H. influenza, E.coli, Pseudomonas and others. ➢ It is a red-brown , tasteless, crystalline powder and very slightly soluble in water. ➢ Its oral absorption is impaired in the presence of food and p-amino salicylic acid. ➢ It is well distributed to almost every body tissue and fluid. ➢ Rifampicin and isoniazid are most effective drugs available for the treatment of tuberculosis. Mechanism of action: ➢ DNA- dependant –RNA polymerase is an enzyme necessary for RNA synthesis. ➢ Rifampicin acts on B-subunit of this enzyme resulting into formation of stable complex. ➢ This is in term cause inhibition of bacterial RNA synthesis, however mammalian enzymes are not affected by this drugs. ➢ Rifampicin is a first line agent. ➢ Since bacterial resistance develops rapidly if rifampicin is taken alone.
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➢ Its combination with either isoniazid or ethambutol is preferably used. However combine use of isoniazid and rifampicin may increase the risk of hepatotoxicity.( rifampicin is microsomal enzyme inducer) Pyrazinamide:
➢ It is chemically similar to INH ➢ It is pyrazine analog of nicotinamide, was developed in 1952. ➢ It is weakly tuberculocidl but more active in acidic medium. ➢ It is highly lethal intracellularly located bacilli as well as to those at sites showing inflammatory response. ➢ It is white, odourless, crystalline poder with a bitter taste and sparingly soluble in water. It is bactericidal at high concentration for rapidly dividing tubercule bacilli and for organisms in macrophages. It has now become a first line drug for the initial 2 months of therapy, when 6 month course are used. ➢ It is an antituberculosis drug invariably employed for the initial treatment in conjugation with isoniazid and rifampicin which it potentiates significantly. Mechanism of action: ➢ Its mechanism of action is still unclear. ➢ It acts probably either by suppressing bacterial protein synthesis or antibacterial action resembles INH inhibit mycolic acid synthesis but by interacting with different fatty acid synthase encoding gene.
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Q – 16. Classify anti TB drugs. Explain second line treatment for TB. ➢ These drugs can be classified as 1) First line agents: Ex-Isoniazid, Rifampin, Pyrazinamide, Ethambutol, Streptomycin
Isoniazid Pyrazinamide 2) Second line agents: Ex- Ethionamide, Thiacetazone, Para amino salicylic acid, Cycloserine, Capreomycin, Kanamycin etc.
❖ Second line agents for treatment of TB. ➢ These drugs have less efficiency and significant toxicity. ➢ These drugs are relatively toxic hence they should be used only when the organism develops resistance to the first line agents.
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Q – 17. Classify Quinolones. Explain mechanism of action of Quinolones. ❖ Classification: ➢ Quinolones can be classified as follow (1) First generation quinolones: Ex. - Nalidixic acid, Cinoxacin
(2) Second generation quinolones (Fluroquinolones): a) First generation fluroquinolones: Ex. - Norfloxacin, Ofloxacin, Ciprofloxacin, Enoxacin
b) Second generation fluroquinolones: Ex. - Sparfloxacin, Lomefloxacin, Gatifloxacin, Moxifloxacin
❖ Mechanism of action: ➢ The quinolones are rapidly bactericidal. ➢ The FQs inhibit the enzyme bacterial DNA gyrase, which nicks double stranded DNA, introduces negative supercoils and then reseal the niked ends. This is necessary to prevent excessive positive superrcoiling of the strands when they separate to permit replication or transcription. Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 1
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➢ The DNA gyrase consist of two A and two B subunits. ➢ A subunit carries out nivking of DNA , B subunit introduces negative supercoils and than A subunit reseal the strands. ➢ FQs bind to A subunit with its strand culting and resealing function. ➢ Recent evidence indicates that in gram positive bacteria the major target of FQ action is similar enzyme-topoisomerase IV which nicks and separate daughter DNA strands. After DNA replication. ➢ The bactericidal action probably results from digestion of DNA by exonucleus whose production is signaled the damaged DNA. ➢ In place of DNA gyrase or topoisomerase IV , the mammalian cells posses an enzyme topoisomerase II, that also removes positive supercoils. Which has law affinity for FQs hence the low toxicity to host cells.
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Q – 18. Explain SAR of Quinolones and write a synthesis of Ciprofloxacin. ❖ SAR of Quinolones:
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❖ Synthesis of Ciprofloxacin:
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Q – 19. Explain SAR and MOA of Sulfonamides. ❖ SAR of Sulfonamides: ➢ General formula for sulfonamides is
(1) The amino and sulfonyl radicles on benzene ring are essential and should be in 1,4 position. (2) Sulfur atom should be directly linked to the benzene ring. (3) Substitution at N1:- In substituted sulfonamide activity varies with the nature of substituent at amino group.
➢ Substitutuent which impart electron rich character to SO2 group, bacteriostatic activity increases. ➢ Heterocyclic substituent leads to highly potent derivative. ➢ Sulfonamides that contain single benzene ring at N1 position are considerably more toxic than heterocyclic ring analogs. ➢ The substitutions at N1 or heterocyclic aromatic nuclei at N1 or N1 phenyl ring affect the binding to plasma protein. ➢ N1 disubstitution in general leads to inactive compounds because one hydrogen atom is essential for ionization of the drug.
➢ Exchange of the -SO2NH- by -SO2C6H4 (p-NH2), -CONH2, -CONHR, -COC6H4R retain the activity, though reduce in most cases. (4) Sustitution at N4:- ➢ The N4 amino group could be modified to produce prodrug which is converted to free amino function in vivo, eg. – Phthalyl and succinyl sulfathiazole.
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➢ The free amino group should be para to the sulfonamide group. Its substitution at ortho or meta position results in compounds devoid of antibacterial activity. (5) The antibacterial activity of sulfonamides is related to PKa value. Maximum activity would be found to those having PKa value between 6.0 and 7.5. (6) Replacement of benzene ring by other ring system or introduction of additional substituent on it decreases or abolishes activity.
❖ Mechanism of action: ➢ Sulfonamides are structurally similar to p- amino benzoic acid (PABA) which is growth factor, PABA if essential for the synthesis of folic acid which is subsequently biotransformed into DNA and RNA. ➢ Mammals and bacteria require folic acid. Mammals get folic acid preformed from food whereas bacteria synthesize it de novo from PABA. ➢ At physiological pH, folic acid exists as a dianion which can not cross the bacterial cell wall by passive diffusion. It requires active transport and bacteria lacks this mechanism, therefore they have to synthesize folic acid from PABA. ➢ Sulfonamide and sulfone act as competitive inhibitor for the incorporation of PABA to form dihydrofolic acid. ➢ Sulfonamide inhibit the enzyme dihydropteroate synthase, an important enzyme needed for the biosynthesis of folic acid derivative and ultimately the thymidine required for DNA. ➢ They do so by competing at the active site with p- amino benzoic acid (PABA), a normal structural component of folic acid derivative. PABA is otherwise incorporated in to developing tetrahydrofolic acid molecule by enzyme catalyzed condensation with 6- hydroxy methyl -7, 8 – dihydropterin pyrophosphate to form 7, 8 – dihydropteroate.
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➢ Some bacteria resulting in incorporation of sulfonamide as a false metabolite.
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Q – 20. Write synthesis and uses of Sulphacetamide and Sulphamethoxazole. (1) Sulfacetamide ❖ Synthesis:
❖ Uses: ➢ It is used to treat bacterial eye infection such as conjunctivitis.
(2) Sufamethoxazole ❖ Synthesis:
❖ Uses: ➢ It is used to treat wide variety of bacterial infection such as middle ear, urinary tract, respiratory and intestinal infections. ➢ It is used to prevent and treat a certain type of pneumonia.
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Q – 21. Define Antifungal drugs and explain antifungal antibiotics. ❖ Antifungal drugs: These are defined as the agents which are used to treat different types of fungal infection i.e. mycoses. ❖ Antifungal antibiotics: 1) Polyene antibiotics : Nystatin, Amphotericin – B, Natamycin 2) Griseofulvin (1) Polyene antibiotics ➢ They are also called membrane distruptors. ➢ The discovery of the polyene antifungal agent, however provided a break through into both a new class of antifungal agents and the first drug to be effective against deep – seated fungal infection. Chemistry and structure of polyenes: ➢ As the name indicates these compounds contain unsaturated carbon ring or chains. ➢ They all are characterized by the presence of a large ring containing a lactone group (macrolide lactone) and a hydrophobic region coupled with conjugated polyene system of four to seven double bonds. ➢ Many of them contain a glycosidically linked aminosugar for example an aminodeoxy hexose is present in amphotericin – B and nystatin. Mechanism of action: ➢ The polyenes have an affinity for sterol containing membranes, insert into the membrane and disrupt membrane functions by following mechanism, • Formation of bond between lipophilic segment of polyene antibiotics and sterol. • Autoxidation of drug produce free radical which cause increase in cell permeability. • Intermolecular hydrogen bonding among –OH, -CO- and amino functional group which disrupt symport (transport across the membrane) activity. ➢ The membrane of cell treated with polyenes becomes leakly and eventually the cell die because of the loss of essential cell constitutes such as ions and small organic molecules. (i) Nystatin
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➢ It was the first clinically useful polyene antifungal antibiotic. ➢ It is conjugated hexaene isolated from cultures of bacterium Streptomyces noursei in 1951. ➢ Nystatin is an effective topical antifungal against a wide variety of organisms and is available in variety of creams and ointment. ➢ The aglycone portion of nystatin is called nystatinolide. ➢ It consists of 38-membered macrolide lacton ring which have 6 double bonds. ➢ Nystatin is toxic to be used systemically but because very little drug is absorbed following oral administration; it may be administered by mouth to treat fungal infection of mouth and GIT. ➢ Nystatin is effective specially against Candida, Microsporum, Trichophyton, Leishmania, B. dermatidis, H. capsulatum, T. vaginalis and dermatophytes. (ii) Amphotericin – B
➢ It is mixture of two compounds A & B. ➢ Amphotericin B was first isolated from Streptomyces nodosus. ➢ It consists of seven conjugated double bonds, an internal ester, a free carbonyl group and glycoside side chain with a primary amino group. ➢ It contains a free carbonyl group and a lactone(6-membered) ring D- mycosamine. ➢ The conjugated systems are usually all trans configuration so that the ring contain a plznner lipophillic segment and a less rigid hydrophilic portion. ➢ Amphotericin B is amphoteric forming soluble salt in both basic and acidic environment. ➢ Amphoteric B has low enough toxicity to mammalian cells to permit IV administration however it is nevertheless a very toxic drug and must be used with caution. ➢ It is effective against aspergillus fumigates, b. dermatitis, candida spp., h.capulatum, rizopus species and mycobacterium lapre. ➢ It is used topically to meet external ocular infections( i.e mycotic conjuctivities) ➢ It may be used IV or subcutaneously in the treatment of fungal corneal ulcer or in the treatment of endopthalmitis.
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(2) Griseofulvin
➢ It is also known as Grisovin used to treat fungal infection of skin. ➢ It is derived from the mould Penicillium griseofulvum. ➢ It is used orally to treat superficial fungal infection: primarily fingernail and toenail infections but it does not penetrate skin or nails if used topically. ➢ When given orally, griseofulvin becomes incorporated into keratin precursor cells and ultimately into keratin, which can not then support fungal growth. ➢ Gresiofulvin enters the dermatophytes through energy dependent transport process and bind to fungal microtubules, which interfere with function of mitotic spindle and thereby inhibit cell division. ➢ Griseofulvin also may interfere directly with DNA replication.
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Q – 22. Classify Antifungal drugs and explain azoles antifungal. ❖ Classification of antifungal drugs: (1) Fatty acids: Natural sebum, Propionic acid, Zinc propionate, Sodium caprylate, Zinc caprylate. (2) Antifungal antibiotics a) Polyene antibiotics: Nystatin, Amphotericin B
Nystatin b) Griseofulvin
Griseofulvin (3) Azoles a) Triazoles: Fluconazole, Itraconazole
Fluconazole
b) Imidazoles: (i) Topical: Clotrimazole, Econazole, Miconazole (ii) Systemic: Ketoconazole
Clotrimazole
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(4) Allyl amines and other squalene epoxidase inhibitors: Naftifine, Tarbinafine, Butenafine, Tolnaftate.
Naftifine Tolnaftate
(5) Antimetabolites (fluorinated pyrimidines): Flucytosine
Flucytosine
(6) Chitin synthetase inhibitors: Nikomycin Z (7) Inibition of cell wall biosynthesis: Anidulafungin, micafungin (8) Peptides/proteins: Cispentacin
❖ Azoles: ➢ Imidazole derivatives are associated with many therapeutic fields. ➢ Some have been employed as anthelmintics, antibacterial and antiprotozoal activities. ➢ Azoles antifungal agents are the largest class of antimycotics available today. ➢ Some are primarily used topically to treat superficial dermatophytic and yeast infections whereas other are administered orally for the treatment of systemic fungal infection.
Structural features: ➢ The first member of class were highly substituted immidazoles such as clotrimazole and miconazole. ➢ Structure activities studies revealed that the imidazole ring could be replaced with a bio-isosteric 1,2,4-triazole ring without adversely affecting the antifungal properties of the molecule. ➢ It contain five membered aromatic ring containing either two or three nitrogen atoms. • Imidazole ring- 2 nitrogen atoms
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• Triazole ring- 3 nitrogen atoms ➢ In both the cases azole ring is attached through N1 to a side chain containing atleast one aromatic ring.
Mechanism of action: ➢ All the azoles act by inhibiting ergosterol biosynthesis through inhibition of the 14 α demethylase. ➢ The basic N 3 atom of azole form a bond with the heme ion of cytochrome-45 prosthetic group in the position normally occupied by the activated oxygen. ➢ Inhibition of the 14α demethylase results in accumulation in the fungal cell. ➢ Membrane of steroids still wearing a 14α methyl group ➢ These sterols do not have the exact shape and physical properties of normal membrane sterol, ergosterol. ➢ This result in permeability changes, leakly membranes and malfunction of membrane embedded proteins. ➢ These effects taken together lead to fungal cell death. ➢ In general higher concentration of the azoles are needed to inhibit the mammalian enzyme, this provides selectivity.
Structure and uses of important drugs: 1. Ketoconazole: Structure:
Uses: ➢ It is recommended for the treatment of selected non maningeal fungal infection in non immunosupressed patients including paracoccidiomyosis and mucosal candidiasis infection.
2. Clotrimazole: Structure:
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Uses: ➢ It is used primarily as topical agent. ➢ It cures dermatophyt infections cutaneous candidiasis, vulvo vaginal candidiasis. ➢ It is used in ring warm and other skin infections.
3. Fluconazole: Structure:
Uses: ➢ It is the newest member od the azole family and is a fluorinated bis-triazole. ➢ The drug is indicated for the treatment of systemic candida infections and the treatment of cryptococoal meningitis. Both of this serious infections occur frequently in the AIDS patients. ➢ It can be used successfully against eshophageal, urinary tract, peritoneal and other systemic infection.
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Q – 23. Write synthesis and uses of Miconazole and Tolnaftate.
❖ Miconazole Synthesis:
Uses:
➢ Miconazole is a potent antifungal imidazole derivative that may be used topically, intravenously or intrathecally.
➢ It is used to treat skin infections such as athlete’s foot, jock itch, ringworm and other fungal skin infections (candidiasis).
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❖ Tolnaftate
Synthesis:
Uses:
➢ It is a synthetic thiocarbamate used as an anti fungal agent. ➢ It is used to treat fungal infections such as jock itch, athlete’s foot and ringworm.
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Q – 24. What is amoebiasis? Write a note on antiamoebic agents. ❖ Amoebiasis:
❖ Antiamoebic agents: ➢ These are the agents which are used to treat the amoebiasis, infection due to parasite Entamoeba histolytica.
❖ Classification: ➢ They are classified as
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 4
Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 5
Medicinal chemistry- III (BP601TP)
Q – 25. Write a note on anthelmintic drugs. ❖ Anthelmintics
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 1
Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 2
Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 3
Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 4
Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 5
Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q – 26. Write synthesis and uses of Metronidazole and Mebendazole. ❖ Metronidazole Synthesis:
Uses: ➢ It is widely used in the treatment of many anaerobic and certain protozoan and parasitic infections.
❖ Mebendazole Synthesis:
Uses: ➢ It is an Anthelmintic drug. ➢ It is used to treat infections caused by worms such as whipworm and pinworm.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q – 24. Define and classify antiviral agents. Explain purine nucleosides and nucleotides. ❖ Antiviral agents: Antiviral agents are substance used in the treatment and prophylaxis of disease caused by viruses.
❖ Classification: 1. Purine nucleosides and nucleotides: Acyclovir, Valcyclovir and Gancyclovir
Acyclovir Gancyclovir
2. Pyrimidine nucleosides and nucleotides: Idoxuridine, Trifluridine, Ribaverin etc.
Idoxuridine Trifluridine
3. Thiosemicarbazon: Methisazone
Methisazone
4. Adamantane amines: Amantadine, Rimantadine, Somantadine
Amantadine Rimantadidne
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
5. Interferons
6. Miscellaneous agents: Ureas and thioureas, guanidines and biguanidines, immunoglobulin, antibiotics
❖ Purine nucleosides and nucleotides: 1. Acyclovir: • It is synthetic purine nucleoside analog. • It is most effective series of acyclic nucleosides that posses anti viral activity. Mechanism of action: • Acyclovir is a synthetic analog of deoxyguanosine in which the carbohydrate moiety is acyclic. • The mechanism of acyclovir consist of three consequtive mechanism i. Conversion of the drug to active acyclovir monophosphate within cell by viral thymidine kinase then it converted into di and triphosphate by normal cell enzyme called guanosine monophosphate kinase. Ultimately increase utilization of thymidine kinase (viral) for other than its normal utilization in virus. This phosphorylation reaction occurs faster within cell infected by herpes virus than normal cell because acyclovir is poor substrate for normal thymidine kinase. ii. In second mechanism, viral DNA polymerase is competitively inhibited by acyclovir triphosphate, is incorporated into viral DNA chain during DNA synthesis. Because acyclovir triphosphate lacks the 3’-hydroxyl groups of cyclic sugar, it terminates firther elongation of DNA chain. iii. Third mechanism of action depend upon preferential uptake of acyclovir by herpes infected cells as compared to uninfected cells.
• The affinity of viral thymidine kinase enzyme for acyclovir is about 200 hundred times greater than that of mammalian enzyme for the drug.
Uses: • It can be used orally, topically and intravenously. • It is effective against herpes virus infection, herpes zoster infection and infections caused by varicella zoster and cytomegalovirus.
Adverse Effects: • It includes nausea, headache, amnesia, hypotension, tremors and comma. • Local irritation, ulceration and burning may occur.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
2. Gancyclovir • It is analogue of acyclovir, with an additional hydroxymethyl group on the acyclic side chain. • This structural modification maintains activity against HSV (Herpes Simplex Virus) and VSV (Vesicular Stomatitis Virus) possessed by acyclovir greatly increase the activity against CMV. • Due to its high toxicity, it is only used in life or slight threatening infections with CMV and AIDs. • Its mechanism of action is similar as acyclovir.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q – 28. What is QSAR? Give a detailed note on Hansch model. ❖ QSAR ➢ QSAR approach attempts to identify and quantify the physicochemical properties of a drug and to see whether any of these properties has an effect on the drug’s biological activity by using a mathematical equation. ❖ Hansch model
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Topless scheme
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q – 29. Write a note on Hammett substitution constant (electronic parameter) used in QSAR studies.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 3
Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q – 30. Write a detailed note on Combinatorial Chemistry.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 2
Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 3
Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 4
Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 5
Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
Q – 31. Classify anti HIV drugs. Write a note on reverse transcriptase inhibitors. ➢ These are antiretroviral drugs used to treat HIV infection or AIDS. ❖ Classification: (1) Reverse transcriptase inhibitors a) Nucleosides reverse transcriptase inhibitors (NRTI): Zidovudine, Didanosine, Zalcitabine, Lamivudine
Zidovudive Didanosine Zalcitabine Lamivudine
b) Non-nucleoside reverse transcriptase inhibitors (NNRTI): Loviride, Delaveridine
Loviride Delaveridine
(2) HIV protease inhibitors: Saquinavir, Indinavir, Ritonavir
Saquinavir Indinavir
(3) Integrase inhibitors: Zintevir (4) HIV entry inhibitors: a novel target (5) Chemokine receptor binders: Bicyclam (6) vaccines
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
❖ Reverse transcriptase inhibitors (RTIs): ➢ RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses. ➢ When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double stranded viral DNA. ➢ The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation, to produce virus. ➢ RTIs block reverse transcriptase’s enzymatic function and prevent completion of synthesis of the double stranded viral DNA, thus preventing HIV from multiplying. ➢ RTIs can be further divided into two classes.
(a) Nucleoside reverse transcriptase inhibitors (NRTIs): ➢ All these classical antiretroviral agents are 2’, 3’ dideoxy nucleoside analogues. ➢ These compound share a common mechanism of action in inhibiting the reverse transcriptase of HIV. ➢ Because reverse transcriptase acts early in the viral infection sequence, inhibitions of the enzyme block acute infection of cells. ➢ They are only weakly active in chronically infected ones.
Zidovudine ➢ It is 3’ azido – 3’- deoxythymidine, an analogue of thymidine that possess antiviral activity against HIV-1, HIV-2, HTLV-1 and number of other retrovirus. ➢ It was discovered in 1978 as an intermediate in the preparation of amino acid analogues of thymidine. ➢ Zidovudine has greater selectivity affinity for RT than for human DNA polymerase.
Didanosine ➢ It is 2’, 3’ – dideoxyinosine, a synthetic Purine nucleoside analogue that is bioactivated to 2’, 3’ – dideoxy – ATP by host cellular enzyme. ➢ Its metabolite accumulates intracellularly, where it inhibits RT and is incorporated into viral DNA to cause chain termination in HIV infected cells. ➢ Didanosine is generally well tolerated with minimal haematological toxicity, peripheral neuropathy and pancreatitis.
Zalcitabine ➢ It is chemically 2’3’ – dideoxycytidine.
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Faculty of Pharmacy Medicinal chemistry- III (BP601TP)
➢ It is an oral medication used for the treatment of infections with the HIV.
(b) Non – nucleoside reverse transcriptase inhibitors (NNRTIs): ➢ Unlike the nucleoside antimetabolites, the NNRTIs do not require bioactivation by kinase to yield phosphate esters. ➢ They are not incrporated in DNA chain. ➢ Instesd they bind to an allosteric site that is distinct from the substrate binding site of RT. ➢ The inhibitor can combine with either free or substrate bound enzyme, interferring with action of both. ➢ Such binding distorts the enzymes so that it can not form the enzyme substrate complex at its normal rate. ➢ Increasing substrate concentration does not reverse these effects. Hence NNRTIs exhibit a classical noncompetitive inhibition pattern with the enzyme. ➢ They inhibit the RT of retrovirus HIV-1 and do not inhibit Rt of other retro virus including HIV-2 and Simian Immunodefficiency Virus (SIV). ➢ These drugs have high therapeutic index (in contrast to NRTIs) and do not inhibit mammalian DNA polymerase.
Loviride ➢ It is chemically 2-[(2-acetyl-5-methylphenyl)amino]-2-(2,6-dichlorophenyl) acetamide. ➢ It is active against HIV.
Delaveridine ➢ It is chemically 1-[3-(isopropylamino)-2-pyridyl]-4-[(5-methanesulfonamido indol-2-yl) carbonyl] piperazine. ➢ It is used along with other medications to treat HIV infection.
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