Multi-conformational frame from molecular dynamics as a structure-based pharmacophore model for mapping, screening and identifying ligands against PPAR-γ: a new protocol to develop promising candidates.

Despite intensive research on clinical and molecular factors, the development of antidiabetic drugs in the last few decades is decelerating and as a result, the number of drugs approved by the US FDA is reduced. Hence, there is a persistent need for the innovative development of novel anti-diabetic drugs. Recent studies have provided ample proof that the peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor and its co-activator PGC-1 alpha may serve as good candidates for the treatment of several metabolic disorders. Therefore, in this study, 50 ns molecular dynamics (MD) simulations of the ligand-receptor complex were carried out and the most populated cluster of rosiglitazone bound to crucial amino acids during dynamics studies were selected to generate multi-conformation frame and further dynamic pharmacophore models. Finally, three pharmacophore models were generated, and 10 hits were retrieved as final lead candidates by virtual screening of ZINC database and molecular docking. The study reveals that the amino acids Met364, Lys367, His449, Leu453, Leu469, and Tyr473 play a crucial role in the binding of the compounds at the active site of PPARγ and the selected compounds from the ZINC database showed promising binding as compared to rosiglitazone. Further, ADMET studies were carried out to define the pharmacokinetic properties of promising PPARγ ligand candidates.Communicated by Ramaswamy H. Sarma.

4-Cyclohexyl-1-substituted-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones: novel class of H1-antihistaminic agents.

A series of novel 1-substituted-4-cyclohexyl-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones were synthesized by the cyclization of 3-cyclohexyl-2-hydrazino-3H-quinazolin-4-one with various one carbon donors. When tested for their in vivo H1-antihistaminic activity on guinea-pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. The compound 4-cyclohexyl-1-methyl-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (72.96% protection) when compared to the reference standard chlorpheniramine maleate (71.00% protection). The compound II shows negligible sedation (9%) when compared to chlorpheniramine maleate (30%). Hence, it could serve as prototype molecule for further development as a new class of H1-antihistamines.

Synthesis of novel 3-butyl-2-substituted amino-3H-quinazolin-4-ones as analgesic and anti-inflammatory agents.

A variety of novel 3-butyl-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 3-butyl-2-hydrazino-3H-quinazolin-4-one with various aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. The compound 3-butyl-2-(1-methylbutylidene-hydrazino)-3H-quinazolin-4-one (AS3) emerged as the most active analgesic agent. Compound 3-butyl-2-(1-ethylpropylidene-hydrazino)-3H-quinazolin-4-one (AS2) emerged as the most active anti-inflammatory agent and is moderately more potent when compared to the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared to aspirin.