1. Organic Chemistry 4 th Edition Paula Yurkanis Bruice Irene Lee Case Western Reserve University Cleveland, OH ©2004, Prentice Hall Chapter 30 The Organic Chemistry of Drugs Discovery and Design

2. A drug is any absorbed substance that changes or enhances a physical or psychological function in the body A proprietary name (trade name or brand name) identifies a commercial product and distinguishes it from other products Each drug is also given a generic name that any pharmaceutical company can use to identify the product

3. Some Examples of Drugs Trimoxamoxicillin ® Proprietary name Generic name antibiotic Premarinconjugated estrogens hormone replacement therapy ®

4. The goal of the medicinal chemist is to find compounds that have potent effects on given diseases, with minimum side effects A naturally occurring drug can serve as a prototype (lead compound) Analogs of the lead compounds are synthesized to improve the therapeutic properties or side effects

5. Molecular Modification to Improve the Therapeutic Properties of Cocaine local anesthetic, but bad effect on the central nervous system retains the local anesthetic property

6. Anesthetics Obtained through Molecular Modification

7. Replacing the ester linkage of procaine with an amide linkage led to procainamide hydrochloride Active as a cardiac depressant Active as a local anesthetic Used clinically as an antiarrhythmic

8. Molecular Modification of Morphine Morphine and all the compounds prepared by molecular modification of morphine have a structural feature in common

9. Molecular Modification of Codeine Dextromethorphan is the major ingredient in most cough medicines

10. Random Screening The lead compound for the development of most drugs is found by screening thousands of compounds randomly A random screen is a search for a pharmacologically active lead compound without any information about what structures might show activity

11. The tranquilizer Librium was discovered accidentally

12. Structural modification of Librium leads to the generation of other tranquilizers

13. Many drugs exert their physiological effects by binding to a specific cellular binding site called a receptor Excess histamine in the body causes the symptoms associated with the common cold and allergic responses

14. Antihistamines alleviate the action of histamine by binding to the histamine receptor

15. Acetylcholine is a neurohormone that enhances peristalsis, wakefulness, and memory Cholinergic receptors are structurally similar to the histamine receptors The antihistamine diphenhydramine has been used to treat insomnia and motion sickness

16. 4-Methylhistamine is used as a lead compound to develop antiulcer drugs

17. In screening modified compounds, it is possible to find a compound with completely different pharmacological activity than the lead compound an antibiotic a drug with hypoglycemic activity

18. Molecular modification of promethazine leads to the discovery of an antipsychotic drug

19. Drugs as Enzyme Inhibitors Penicillin destroys bacteria by inhibiting the enzyme that synthesizes bacterial cell walls

20. penicillinase Bacteria develop resistance to penicillin by secreting penicillinase which destroys pencillin

21. Chemists have developed drugs that inhibit penicillinase Administering penicillin and the sulfone in combination results in drug synergism

22. Mechanism of Penicillinase Inhibition by Sulfone

23. The following two antimicrobial agents are given in combination to treat tuberculosis

24. The therapeutic index is the ratio of the lethal dose to the therapeutic dose The higher the therapeutic index, the greater is the margin of safety of the drug

25. A Suicide Substrate that Inactivates Transamination

26. Approach in Rational Drug Design To correlate the known physical or chemical property of a series of compounds with biological activity To correlate the property of a drug with a specific activity To use the existing knowledge to design compounds that possess the desirable activity

27. The biological activity of a drug depends on two properties distribution binding Distribution coefficient: the ratio of the amount dissolving in 1-octanol to the amount dissolving in water Compounds with a lower distribution coefficient cannot penetrate the cell membrane Compounds with a higher distribution coefficient cannot cross the aqueous phase

28. The technique of relating a property of a series of compounds to biological activity is known as a quantitative structure–activity relationship (QSAR) a 2,4-diaminopyrimidine potency = 0.8  – 7.34  – 8.14  measures the electron-donating or electron-withdrawing properties of R and R’  measures the hydrophobicity of R and R’

29. In a search for a new analgesic, HA indicates whether R is a hydrogen bond acceptor and where B is a steric factor Analysis indicated that the vinyl substituted compound should be prepared

30. Utilization of Computer Molecular Modeling in Drug Design

31. Search for New Drugs by Mass Production Combinatorial Organic Synthesis This approach has been used to create a library of benzodiazepines

33. Antiviral Drugs These nucleoside analogs interfere with DNA or RNA synthesis