Vidya Bhushan Lohray

Novel Coumarin Derivatives of Heterocyclic Compounds as Lipid-Lowering Agents §

Coumarin derivatives of different heterocycles (5,7a-i, 10 and 11) were designed based on cyclisation of 2-ethoxy-3-phenylpropanoic acid and 2-benzylmalonic acid as novel lipid-lowering agents and their preliminary in vivo screening indicates 7c has moderate triglyceride-lowering activity.

Novel phthalazinone and benzoxazinone containing thiazolidinediones as antidiabetic and hypolipidemic agents

We report here the synthesis of a series of 5-[4-[2-[substituted phthalazinones-2(or 4)yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and 5-[4-[2-[2,3-benzoxazine-4-one-2-yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and their plasma glucose and plasma triglyceride lowering activity in db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. In vitro and in vivo pharmacological studies showed that the phthalazinone analogue has better activity. PHT46 (compound 5a), the best compound in this series, showed better in vitro PPARgamma transactivation potential than troglitazone and pioglitazone. In insulin resistant db/db mice, PHT46 showed better plasma glucose and triglyceride lowering activity than the standard drugs. Pharmacokinetic study in Wistar rats showed good systemic exposure of PHT46. Subchronic toxicity study in Wistar rats did not show any treatment-related adverse effect.

Association with coregulators is the major determinant governing peroxisome proliferator-activated receptor mobility in living cells.

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives

A series of pyrimidinone derivatives of thiazolidinediones were synthesized. Their biological activity were evaluated in insulin resistant, hyperglycemic and obese db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. PMT13 showed the best biological activity in this series. PMT13 (5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione) showed better plasma glucose, triglyceride and insulin-lowering activity in db/db mice than rosiglitazone and pioglitazone. PMT13 showed better PPARgamma transactivation than the standard compounds. Pharmacokinetic study in Wistar rats showed good systemic exposure of PMT13. Twenty-eight day oral toxicity study in Wistar rats did not show any treatment-related adverse effects.

Novel pyrrole-containing hypoglycemic and hypotriglyceridemic compounds*

Several substituted α-alkoxy phenyl propionic acids were synthesized, and their hypotriglyceridemic properties were evaluated in Swiss albino mice. Some of the compounds showed excellent triglyceride- and cholesterol-lowering properties even at a dose of 1 mg/kg. 2,5-Substituted pyrrole-containing heterocycles were among the most potent alkoxy propionic acid class of compounds. These compounds also showed excellent antidiabetic activities in animal models.

Synthesis and Cyclooxygenase-2 (COX-2) Inhibiting Properties of 1,5 - Diarylpyrazoles Possessing N-Substitution on the Sulfonamide (-SO2NH2) Moiety †

A number of novel 1,5-diarylpyrazoles possessing N-substitution on the sulfonamide (-SO2NH2) moiety were synthesized and tested for COX-1/COX-2 inhibition in vitro. Many of these 1,1-dioxo-2,3- dihydrobenzo(d)isothiazolyl substituted 1,5-diarylpyrazoles, where the SO2NH2 group was a part of the fused ring, showed COX inhibitory activity. Few of them were identified as selective COX-2 inhibitors. Structure Activity Relationship study within the series are discussed.

Novel anti-infective compounds

A set of substituted piperazinyloxazolidinone derivatives has been studied for their antibacterial activity in a few gram-positive bacteria. The structural modifications have provided a superior compound than linezolid, the only drug of this class in the market at present.