LIPOPHILICITY BEHAVIOR OF MODEL AND MEDICINAL COMPOUNDS CONTAINING A SULFIDE, SULFOXIDE, OR SULFONE MOIETY

This study was designed to unravel lipophilicity changes associated wi th the oxidation state of the S-atom in model compounds, drugs, and me tabolites, special attention being given both to intermolecular and in tramolecular effects. The methods used were experimental (potentiometr y, CPC, and shake-flask techniques to measure lipophilicity, C-13-NMR spectroscopy to investigate tautomeric equilibria) and computational ( quenched molecular dynamics and molecular lipophilicity potential). Si mple, monofunctional model compounds were used to assess intermolecula r forces, as revealed by the Delta log Poct-alk and Delta log Poct-chf parameters. Drugs and their metabolites proved to be good probes to s tudy intramolecular effects in both neutral and anionic forms, as reve aled by the difference between calculated and experimental log P-oct v alues (the diff(log Pexp-calc) parameter). Sulindac and its metabolite s showed a normal partitioning behavior, whereas the lipophilicity of sulfinpyrazone and its metabolites was markedly affected by tautomeric and conformational equilibria.