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Ab initio molecular orbital (MO) and density functional studies have been carried out on the keto-enol tautomerization process in thiazolidinediones to understand the mechanism of rapid racemization observed in these systems. MP2(full)/6-31+G* results on model thiazolidinedione 1 indicate that the energy difference between keto and enol tautomers is 24.04 kcal/mol, which is larger than that in acetaldehyde (16.23 kcal/ mol). Neither the ring strain in 1 nor the electron delocalization in its tautomers is significant enough to facilitate rapid racemization through this mechanism. Reversible S-oxide formation increases the acidity of the hydrogen at the chiral center as well as provides an alternative path for tautomerization, suggesting that such a mechanism is responsible for the rapid racemization observed under physiological conditions. † NIPER communication no 275.

Recent trends in drug discovery include methods to identify dual and triple activating drugs. This approach is being successfully employed in malaria, cancer, asthma, insulin resistance, etc. Molecular field analysis has been employed in correlating pharmacological data and field parameters. In this paper we introduce the concept of additivity of molecular fields to correlate molecular fields of dual activators and their pIC(50) values. PPARalpha and PPARgamma dual activators, which affect hypertriglyceridemia and hyperglycemia, have been chosen to validate the molecular field additivity concept. Three CoMFA models namely alpha-model, gamma-model and dual-model have been developed. The validity of this concept has been ascertained by (a) comparing contour maps, (b) by comparing CoMFA results with FlexX docking results and (c) by analyzing newly designed molecules.

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