Modeling molecular interactions of propounded pyrazole based drug candidates against bacterial DNA gyrase: Validation by syntheses and biological studies

Abstract

A class of nitrogen-based heterocycles, pyrazoles and their derivatives, are cardinal agents in the field of pharmacology. Here, we have conducted in silico studies on newly designed pyrazole based drug molecules, thereby revealing their activities and interaction behaviors when docked against S. aureus DNA gyrase upon comparison with a standard drug ciprofloxacin and previously reported few compounds. The drug likeliness of the compounds was analyzed using QikProp module of Maestro 11.5 (Schrödinger) through ADME (Absorption, Distribution, Metabolism and Excretion) analysis. Among the predicted compounds, we have synthesized four pyrazole derivatives; namely 5-(3, 5-dimethyl-1H-pyrazol-1-yl) 1,3-benzoic acid, 5-(3, 5-dimethyl-1H-pyrazol-1-yl) 1,3-benzenedicarboxylic acid, 4-(4-methyl-1H-pyrazole-1-yl) benzoic acid and 1-(4-carboxyphenyl)-1H-pyrazole-4-carboxylic acid. All the four compounds are characterized by 1H and 13C NMR, IR, UV, and mass spectrophotometry. We have successfully tested the same compounds for anti-microbial activities involving testing with standard bacterial as well as fungal strains. Anti-bacterial activity testing was performed against two Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis and three Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica. Anti-fungal activity was carried out against a well-known fungal strain Candida albicans. The observed antimicrobial activities are in well agreement with the docking results. The DFT study was also carried out to compare the conformational stability of the optimized structures and docked-pose of the four molecules.