Methylene resonance and conjugation effects in 3-(4-bromophenyl)-5-(substituted phenyl)-4,5-dihydroisoxazoles: Synthesis, spectral QSAR studies, in-silico and in-vitro activities evaluation

Abstract

In this study we report the synthesis and biological evaluation of series of 3-(4-bromophenyl)-5-substituted phenyl-4,5-dihydroisoxazoles (1-8). These 3-(4-bromophenyl)-5-substituted phenyl-4,5-dihydroisoxazoles successfully synthesised from 4-bromophenyl chalcone derivatives with hydroxylamine hydrochloride by condensation cum cyclisation method, and their structures are confirmed by FT-IR, ¹H, and ¹³C NMR spectroscopy techniques. The characteristic spectral frequencies and chemical shifts of these isoxazolines were correlated with Hammett substituent constants and F, R parameters by QSAR analysis. The antimicrobial activity of synthesised isoxazolines (1-8) was assessed invitro against two Gram-positive and two Gram-negative bacterial strains, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Klebsiella pneumonia and two fungal strains Candida aureus, Candida albicans by Kirby-Bauer disc diffusion method. The molecular structure of 3-(4-bromophenyl)-5-substituted phenyl-4,5-dihydroisoxazoles was explored using Density Functional Theory (DFT) at the B3LYP/6-311G(d,p) level of theory. The simulations yield information about total energy, frontier molecular orbitals (HOMO and LUMO), and molecular electrostatic potential (MEP) surfaces. Molecular docking investigation of 3-(4-bromophenyl)-5-substituted phenyl-4,5-dihydroisoxazoles (1–8) against the bacterial protein DNA gyrace (PDB ID: 4URO) reveals that compound 8 has the highest binding affinity value (-6.68 kcal/mol). The findings of the ADMET (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) study help the ongoing development of pharmacologically active medicines.