Synthesis, spectral QSAR, molecular docking, DFT, ADMET studies and anti-microbial activity evaluation of some benzodioxin pyrazolines

Abstract

A series of nine 4,5-dihydro-3-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-1,5-(substitutedphenyl)-1H-pyrazolines were synthesized by treating (E)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylprop-2-en-1-ones with phenyl hydrazine hydrochloride in the presence of sodium acetate via cyclization reaction by cyclo-condensation process. These synthesized products were characterized by FT-IR, ¹H and ¹³C NMR spectral data. The infrared spectral frequencies C=N, N-N and C-X (ν, cm^-1), along with NMR chemical shifts (δ, ppm) of H_a, H_b, H_c protons, and the C=N, C-N, C-X, CH₂ carbons of 4,5-dihydro-3-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-1,5-(substitutedphenyl)-1H-pyrazoline have been assigned and related to utilizing single and multi-regression analysis with Swain-Lupton's parameters and Hammett substituent constants. The in-vitro antimicrobial assay of all compounds was evaluated with two-gram positive bacterial species: Staphylococcus Aureus, Streptococcus Pneumonia and two-gram negative bacterial species: Pseudomonas aeruginosa, Escherichia coli, fungal species:  Candida albicans, Candida auris. The highest values of zone of inhibition were recorded to compound 1, followed by the compound 4 and 8 exhibits a good zone of inhibition both in bacterial and fungal strains. In-silico analysis like molecular docking studies of potent antibacterial compounds (1, 4 and 8) indicated strong binding affinities to the receptors Streptococcus aureus-7S54, Escherichia coli-9R2Z, Candida albicans-5HW8. Employing DFT(B3LYP) with 6-311G(d,p) basis set for in-silico evaluations confirmed favorable drug-likeness and pharmacokinetic properties for all pyrazolines. The ADMET properties further demonstrated that these compounds possess a good therapeutic application in combating bacterial and fungal infections.