STRUCTURE-GUIDED DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL BENZOTHIAZOLE DERIVATIVES AS DUAL-TARGET ANTIMICROBIAL AGENTS: MOLECULAR DOCKING, DYNAMICS AND GENE EXPRESSION STUDIES

Abstract

To combat antimicrobial resistance, it is important to create a way to disrupt more than one essential pathway of bacteria. A structure-guided rational design, synthesis, and evaluation of 2-arylbenzothiazole derivatives (BT1 BT12) as dual inhibitors of DNA gyrase B and dihydrofolate reductase (DHFR) were carried out in this study. The physicochemical and spectroscopic characterisation, followed by drug-likeness, ADMET, and molecular docking and molecular dynamics analyses, was performed for the characterisation of the derivatives. Antimicrobial activity was measured using selected Gram-positive and Gram-negative bacteria by the use of inhibition zone, Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC). The time-kill activity, inhibition of biofilm, enzyme inhibition, gene expression, cytotoxicity, and haemolysis of lead compounds were further investigated. Benzothiazole (BT9) with 6-fluoro and 4-chloro substituents showed the most promising dual-target binding, antimicrobial activity, and antibiofilm potential in the illustrative derivatives. The molecular-dynamics profiles suggested stable BT9–target complexes, whereas the enzyme inhibition and gene-expression results showed potential for interference with DNA topology and folate metabolism. The cell viability was also relatively high, and there was minimal haemolysis, with the highest selectivity index for BT9. The results indicated the benzothiazole derivatives bearing halogens as possible dual targeting antimicrobial scaffolds, which require further experimental, pharmacokinetic and in vivo investigations.