Development of novel thiazole-based hybrids as DNA gyrase inhibitors: design, synthesis, in silico and in vitro antibacterial evaluation

Novel thiazole-based hybrids (8a–g) and (9a–g) were developed and synthesized to create lead compounds with remarkable antibacterial efficacy. Several analytical methods were used to characterize the synthesized compounds, including NMR, IR, and HR-MS. Molecular docking against the DNA Gyrase B (PDB ID: 6YD9) was studied to have an extensive understanding of the binding interactions of thiazole-based hybrids with the protein of Escherichia coli. The 9e and 9g derivatives demonstrated outstanding in vitro inhibitory efficacy with minimum-inhibitory concentration (MIC) of 6.25 µg/ml and 12.5 µg/ml, respectively, against E. coli. The compound 9c showed better efficacy against S. pyogene (MIC value − 12.5 µg/ml) than the standard drugs. In general, trifluoromethyl-substituted compounds (9a–g) tended to interact with the target protein more than the chloro-substituted compounds (8a–g). The reason is that the lipophilicity generated by the trifluoromethyl group on the thiazepine core helped the molecules to penetrate the bacterial cell wall, which is lipophilic in nature. The increased hydrophobicity of the thiazole substituent contributed to the greater efficacy of compound 9e. Additionally, molecular dynamics simulations were carried out to evaluate the dynamic behavior and stability of the most anticipated compound, 9e, in a complex with the target protein. All synthesized compounds appear non-toxic and non-carcinogenic in living systems, according to in silico ADMET investigations. To aid the development of bioactive molecule design, the structure–activity relationship analysis of the newly synthesized hybrids' remarkable in vitro efficacy against different bacterial strains, is also discussed.