1. Small Molecule Based Drug Design: SAR/Lead Compound Identification Objectives: A drug's pharmacological activity is inherently related to its chemical structure. Upon completion of this lecture the student will know how small changes in chemical structure can lead to significant changes in biological activity, with emphasis on the sulfa drugs. In addition, the student will learn traditional approaches used for the identification of lead compounds in the drug discovery process.

3. Sulfanilamide and general antimicrobial core 1) R = SO 2 NHR' or SO 3 H 2) amino and sulfonyl groups are para 3) anilino (benzene-NH 2 ) amino group may be unsubstituted (or substitutent removed in vivo via metabolism of the drug) 4) replacement of central benzene ring or additional substituents diminishes activity 5) N'-monosubstitution on SO 2 NHR' increase potency (especially with heteroaromatic groups) 6) N'-disubstitution on SO 2 NHR 2 ' leads to inactive compounds

4. General sulfanilamide antidiabetic agent core X: O, S or N incorporated into a heteroaromatic ring or an acyclic structure

5. Diuretics hydrothiazides: 1,3-disulfamyl group R'' is an electronegative group (Cl, CF3, NHR) "High ceiling" type: 1-sulfamyl-3-carboxy groups R'' is Cl, Ph, or Ph-Z (Z = O, S, CO or NH) X located at position 2 or 3 (NHR, OR or SR)

9. Lead Discovery: Drug Metabolism Reduction of Sulindac Reduction of Prontosil

10. Lead Discovery: Clinical Feedback/Observation 1) Tesicam 2) Sudoxicam 3) Piroxicam