Synthesis of novel α-carboxylate-β-bismethylsulfanyl pyrazolyl Schiff base derivatives: Targeting DNA gyrase in antibacterial activity

Abstract

Microbial infections pose a significant threat to human health, often necessitating the use of potent antimicrobial agents for treatment. In this study, a novel series of α-carboxylate-β-bismethylsulfanyl pyrazolyl Schiff base derivatives 6a-d were synthesized and characterized through a combination of analytical techniques, including FT-IR, ¹H and ¹³C NMR, mass spectrometry and single-crystal X-ray crystallography. Through crystallographic scrutiny, it was unveiled that α-carboxylate-β-bismethylsulfanyl pyrazolyl aldehyde 5 is adopted in a monoclinic I2/a space group, while its Schiff base 6c is crystallized in the orthorhombic Pbca space group. The synthesized Schiff base derivatives 6a-d were subsequently assessed for their antibacterial efficacy targeting DNA gyrase protein against one gram-positive bacterium (Staphylococcus aureus MTCC-1430) and three gram-negative bacteria (Escherichia coli MTCC-1610, Pseudomonas aeruginosa MTCC-1934, and Salmonella typhi MTCC-3216). All compounds had substantial antibacterial efficacy against all bacterial strains; however, compound 6b exhibited noticeable efficacy against all gram-negative strains, whereas compound 6d disclosed the highest antibacterial potential against gram-positive strains. The electronic characteristics of the compounds were analysed utilizing density functional theory (DFT), focusing on the determination of HOMO-LUMO energy gaps, molecular electrostatic potential (MEP) maps, and global reactivity descriptors. Molecular docking studies reinforced the promising antibacterial potential of these Schiff base derivatives, revealing favourable binding interactions of the Schiff base derivatives with bacterial target proteins. Additionally, drug-likeness and toxicity assessments were conducted to determine the suitability of these compounds as potential therapeutic agents. Based on these findings, it is suggested that the synthesized derivatives could serve as a promising scaffold for the advancement of novel antibacterial therapies.