Synthesis, antimicrobial, DFT, and in silico pharmacokinetic profiling of nitroaldol quinoline derivatives: A comprehensive exploration for designing potential oral antibacterial agents targeting DNA-gyrase

Abstract

This study presents a thorough exploration of the synthesis, biological activities, and molecular properties of a novel series of β-nitroaldol quinoline derivatives (4a-4i). Structural characterization utilized FTIR, 1H NMR, 13C NMR, and mass spectrometry, providing a comprehensive understanding of the synthesized derivatives. Moreover, anti-microbial properties were evaluated using agar disk diffusion assay against five pathogenic strains, including Gram-negative and Gram-positive bacteria, as well as a fungal strain. Notably, compound 4e demonstrated strong anti-fungal and anti-bacterial activities (MIC = 25 µg/ml). A detailed analysis of molecular orbitals, total density of state, vibrational characteristics, global reactivity descriptors, molecular electrostatic potential, topological QTAIM analysis, and molecular docking provided nuanced insights into the reactivity, electronic properties, and potential interactions of the synthesized compounds. These findings contribute valuable information to the design and synthesis of compounds targeting bacterial DNA-gyrase. Furthermore, in silico predictions using the SwissADME online server indicated that all compounds comply with Lipinski's rule of five, suggesting their potential as orally active drugs. The compounds demonstrated commendable water solubility, passed various filters, and exhibited bioavailability scores, indicating promising oral bioavailability. The percentage of oral absorption ranged from 75.39% to 78.58%, signifying high permeability. Computational analysis of pharmacokinetic parameters revealed favorable characteristics, including gastrointestinal absorption and minimal inhibitory effects on specific enzymes.