Natural products as lead in drug discovery

This presentation discusses in detail about , the way natural products have paved the way forward for the discovery and introduction for new drugs/medicines. The leads from nature are narcotics, antihypertensives, anticancer agents and so

1. NATURAL PRODUCTS AS LEAD IN DRUG DISCOVERY Dr.Vinod B Dept of Pharmaceutical Chemistry St.Joseph’s College of Pharmacy,Cherthala 1

2. INTRODUCTION

3. INTRODUCTION Large No. of Pharmaceuticals derived from natural sources. Few examples are : Artemisnin Alkaloids(Quinine, Morphine, Codeine, ) Antibiotics (Penicillin, Cephalosporin etc ) Anticancer agents ( Paclitaxel ) 3

4. DRUGS AFFECTING CNS-Morphine Alkaloids Morphine isolated in the year 1803 by Serturner ,German Pharmacist Phenanthrene nucleus

5. DRUGS AFFECTING CNS-Morphine Alkaloids Source –Dried latex of Opium poppy Numerous alkaloids- Morphine,Codeine , Narcotine , Papaverine etc

6. MORPHINE AS LEAD Drugs derived from Morphine Codeine ( Methyl Morphine) Heroin ( Diacetyl Morphine) 6

7. MORPHINE AS LEAD 7

8. DRUGS AFFECTING CNS-Morphine Alkaloids Naturally occuring Morphine derivative –Codeine (methyl morphine)analgesic and antitussive action,

9. DRUGS AFFECTING CNS-Morphine Alkaloids Earliest semisynthetic derivative –Heroin( Diacetyl morphine)-used in terminal cancer-

10. DRUGS AFFECTING CNS-Morphine Alkaloids Modification of C-ring of morphine -N- Demethylation and re-alkylation yields N- allyl morphine – nalorphine -morphine antagonist

11. DRUGS AFFECTING CNS-Morphine Alkaloids Further modification– Naloxone –little agonistic activity –retained in therapy for treatment of opiate induced respiratory depression.

12. DRUGS AFFECTING CNS-Morphine Alkaloids Further modification– Naloxone –little agonistic activity –retained in therapy for treatment of opiate induced respiratory depression.

13. DRUGS AFFECTING CNS-Morphine Alkaloids Modification of C ring from Thebaine using Diel’s -Alder reaction- Etorphine and Buprenorphine .

14. DRUGS AFFECTING CNS-Morphine Alkaloids Morphine lacking dihydro furan ring- morphinans -analgesic and additive properties

15. ANTICANCER AGENTS DERIVED FROM NATURE Taxols derived from Yew tree Yew Tree Regarded as the tree of death. 15

16. ANTICANCER AGENTS FROM NATURE Taxus Buccata used for funeral wreaths Used to prepare arrow poison by Celts. 16

17. ANTICANCER AGENTS DERIVED FROM NATURE T.Brevifolia yielded Paclitaxel. 17 Docetaxel derived from Paclitaxel by modifying the ester side chain.

18. DOCETAXEL 18

19. CARDIO VASCULAR DRUGS Mevastatin isolated from Penicillium Citrinium by Dr Akira Endo(1970) 19

20. CARDIOVASCULAR DRUGS Lovastatin isolated from Aspergilus terreus 20

21. CARDIOVASCULAR DRUGS-STATINS MOA 21

22. CARDIOVASCULAR DRUGS S A R of Statins Lactone ring, bicyclic structure & ethylene bridge Size & shape of ring Nature of ester moiety 22

23. CARDIOVASCULAR DRUGS Simvastatin side chain branching Pravastatin lactone ring opening 23

24. CARDIOVASCULAR DRUGS Atorvastatin , Rosuvastatin-Ar ring replaced by other rings 24

25. CARDIOVASCULAR DRUGS-DICOUMAROL Anticoagulant prevents or reduce coagulation of blood, thus prolong clotting time of blood. 25

26. CARDIOVASCULAR DRUGS-DICOUMAROL Dicoumarol is the natural lead 26

27. CARDIOVASCULAR DRUGS-DICOUMAROL Dicoumarol - slow & erratic onset of action Warfarin –potent drug with increased duration of action Acenocoumarol –Rapid onset of action 27

28. CARDIO VASCULAR DRUGS Teprotide -Antihypertensive Ferreira et al isolated a family of peptides from pit viper ( Pothros Jararaca ) venom-inhibited decomposition of Bradykinin by inhibiting ACE 28

29. CARDIO VASCULAR DRUGS Teprotide structure ( nona peptide.) 29

30. ANTI CANCER DRUGS Etoposide & Teniposide Lignan Podophyllotoxin analogues Ancient folk remedy for gout May apple( Podophyllum peltatum ) 30

31. ANTI CANCER DRUGS Podophyllotoxin 31

32. ANTICANCER DRUGS Iso podo phyllotoxins Teniposide Etoposide 32

33. ANTICANCER DRUGS MOA Isopodophyllotoxins causes DNA single stranded and double stranded breaks & DNA protein links. Inhibition of Topoisomerase II Action most prominent in late S or early G-2 phase 33

34. ANTICANCER DRUGS MOA 34

35. ANTICANCER DRUGS Etoposide Refractory testicular tumours,small cell lung cancer Teniposide Acute non lymphocytic leukemia, Hodgkin’s disease, Kaposi’s sarcoma,neuroblastoma 35

36. ANTIMALARIAL DRUGS FROM NATURE Cinchona bark used by South Americans to cure fevers 36

37. ANTIMALARIAL DRUGS Introduced to Europe by Jesuit priests, in 17 th century. Quinine not very potent or long acting. 37

38. ANTIMALARIAL DRUGS FROM NATURE Discovered the antimalarial potency of 4,6 and 8-amino quinolines . Pamaquine,Primaquine , Chloroquine etc 38

39. ANTIMALARIAL AGENTS Artimisnin from Artemesia Annua , a Chinese herb. 39

40. ANTIMALARIAL AGENTS 40 Artemisnin Arteether

41. MACROLIDE ANTIBIOTICS Macrolide -Large macrocyclic lactone,desosamine & cladinose sugars(C5 & C3) Streptomyces species Eg . Erythromycin (natural) -14-member cyclic lactone 41

42. MACROLIDE ANTIBIOTICS Azithromycin (semi synthetic)-15 membered cyclic lactone 42

43. MACROLIDE ANTIBIOTICS Roxithromycin 43

44. MACROLIDE ANTIBIOTICS Clarithromycin 44

45. MACROLIDE ANTIBIOTICS MOA Inhibits protein biosynthesis through interaction with 50 S sub unit of bacterial ribosome. 45

46. β LACTAM ANTIBIOTICS History begins with Sir Alexander Fleming 46

47. β LACTAM ANTIBIOTICS 47

48. β LACTAM ANTIBIOTICS 48

49. β LACTAM ANTIBIOTICS MOA Inhibit D- alanyl -D- alanine transpeptidase activity by forming stable esters with opened lactam ring . Ability to inhibit enzymes depends upon conformational similiarity between amide bond of β lactam ring and peptide link of D- alanyl -D- alanine . 49

50. β LACTAM ANTIBIOTICS CEPHALOSPORINS Antibacterial activity of metabolite of Cephalosporium acremonium detected by Brotzu - isolation of Cephalosporin C by Abraham (1945) 50

51. β LACTAM ANTIBIOTICS General structure 51

52. β LACTAM ANTIBIOTICS Cephalosporins Classification 52

53. CARBAPENEMS Penems not found in nature 53

54. CARBAPENEMS Clinically relevant Imipenem-cilastatin,meropenem and ertopenem 54

55. CURARE ALKALOIDS Skeletal muscle relaxants during surgery developed from studies about South American arrow poisons as well as blow pipe poisons 55

56. CURARE ALKALOIDS King isolated D- tubocurarine from tube curare plant 56

57. CURARE ALKALOIDS D- tubocurarine led to many synthetic bisquarternaries ( eg;decamethonium ) Suxamethonium 57

58. CURARE ALKALOIDS D- tubocurarine (long duration of action) led to drugs like laudexium & atracurium 58

59. NATURAL PRODUCTS AS LEAD 59