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. Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 1 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) 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. Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 1 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 - 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. Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 1 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 Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 1 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: Faculty of Pharmacy, Dr. Subhash Technical Campus, Junagadh. Page 2 Medicinal chemistry- III (BP601TP) 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