1. 1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 9 DRUG DISCOVERY: FINDING A LEAD Part 2: Section 9.4 (Lead compounds from the natural world)

2. 1 © Contents Part 2: Section 9.4 Lead compounds from the natural world 4.The Lead Compound 4.1. Sources of Lead Compounds 4.2. Identification of Lead Compounds 4.3. Lead Compounds from the Natural World (21 slides) -Plant Extracts (4 slides) -Plants and Ancient Records (9 slides) -Herbal Remedies of Olde -Venoms and Toxins (4 slides) -Endogenous Compounds (3 Slides) [25 slides]

3. 1 © Introduction 4 The Lead Compound A compound demonstrating a property likely to be therapeutically usefulA compound demonstrating a property likely to be therapeutically useful The level of activity and target selectivity are not crucialThe level of activity and target selectivity are not crucial Used as the starting point for drug design and developmentUsed as the starting point for drug design and development Found by design (molecular modelling or NMR) or by screening compounds (natural or synthetic)Found by design (molecular modelling or NMR) or by screening compounds (natural or synthetic) Need to identify a suitable test in order to find a lead compoundNeed to identify a suitable test in order to find a lead compound Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound.Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound.

4. 1 © 4.1 Sources of Lead Compounds A) The Natural World B) The Synthetic World C) The Virtual World Plantlife (flowers, trees, bushes) Micro-organisms (bacteria, fungi) Animal life (frogs, snakes, scorpions) Biochemicals (Neurotransmitters, hormones) Marine chemistry (corals, bacteria, fish etc) Chemical synthesis (traditional) Combinatorial synthesis Computer aided drug design

5. 1 © 4.2 Identification of Lead Compounds A) Isolation and purification solvent-solvent extraction chromatography crystallisation distillation B) Structure determination elemental analysis molecular weight mass spectrum infra red ultra violet nmr ( 1 H, 13 C, 2 D) X-ray crystallography

6. 1 © 4.3 Lead Compounds from the Natural World PLANT EXTRACTS

7. 1 © POPPY CAPSULE MORPHINE 4.3 Lead Compounds from the Natural World PLANT EXTRACTS

8. 1 © 4.3 Lead Compounds from the Natural World PLANT EXTRACTS OPIUM - MorphineOPIUM - Morphine CINCHONA BARK - QuinineCINCHONA BARK - Quinine YEW TREE - TaxolYEW TREE - Taxol

9. 1 © 4.3 Lead Compounds from the Natural World PLANT EXTRACTS WILLOW TREE - SALICYLIC ACID COCA BUSH - COCAINE Aspirin Procaine

10. 1 © 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS

11. 1 © ARTEMISININ 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS

12. 1 © ARTEMISININ 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS

13. 1 © ARTEMISININ 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS

14. 1 ©

15. 1 ©

16. 1 © Fe

17. 1 © 4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDS THE BEATONS OF PENNYCROSS

18. 1 © CURE for EPILEPSY Heat a cauldron of water until warm to the touch Add a liberal sprinkling of juicy spiders Produce one pedigree dog Flavour with essence of dog turd Simmer for 20 minutes then enjoy THE BEATONS OF PENNYCROSS

19. 1 © 4.3 Lead Compounds from the Natural World HERBAL REMEDIES OF OLDE Majority may have worked through a placebo effect

20. 1 © 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS Captopril(anti-hypertensive) Teprotide

21. 1 © 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS

22. 1 © Tubocurarine (from curare) 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS

23. 1 © Atracurium (Neuromuscular blocker) Tubocurarine (from curare) 4.3 Lead Compounds from the Natural World VENOMS AND TOXINS

24. 1 © 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS Agonist Agonist

25. 1 © 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS Antagonist Antagonist

26. 1 © 4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDS NATURAL SUBSTRATES FOR ENZYMES Enkephalins Enkephalinase inhibitors Peptides Protease inhibitors