Unraveling biological disparities in configurational isomers of pyrazolyl-dihydrofurans using in vitro, DFT and in silico approach

Abstract

The biological disparities in the high activity of one isomeric form over another have attracted significant interest from medicinal chemists and opened new avenues for synthesizing pure diastereoisomeric drugs.A series of diastereoisomeric pure pyrazolyl-dihydrofurans (6a-6ae) were synthesized in good to excellent yields, and their structures were determined using NMR, LCMS and X-ray crystallography. The difference in the stability of cis and trans isomers has been established using DFT-based studies. Using the serial dilution method, the developed synthetics were evaluated for their bio-efficacy against bacterial and fungal strains. The cytotoxicity was evaluated against mouse fibroblast cells as well as using the seed germination method.All the reactions proceeded smoothly and resulted into cis as the significant isomer; the stability over trans isomer has been established using DFT-based computational studies. Considering 6a and 7a as prototype, the difference in their biological response has been evaluated through in vitro anti-microbial assay. A significant difference in the biological activity has been observed, as the cis isomer (6a) has been found to be more potent over its respective trans isomer (7a) in bacterial assay. As far as the fungal response is concerned, no difference in their biological activity has been observed. The investigated compounds are non-cytotoxic against mouse fibroblast cells and Brassica nigra seeds. The experimentally determined in vitro results have been established using in silico studies.The cis isomer (6a) with an MIC of 3.25 µg/mL has been found to be more potent than the respective trans (7a) form (MIC = 6.25–12.5 µg/mL) when evaluated against different gram positive and negative strains utilized in the present study. However, no disparity in their biological response has been observed in fungal studies.