Synthesis, characterization, antimicrobial and molecular docking studies of 1,3-thiazole derivative

Abstract

There is growing urge to develop treatment systems to cure the diseases and one of the main options is drug development. Heterocyclic thiazole emerges as one of the most frequently reported in those fields. Since thiazole derivatives have been recognized in various biologically active agents, two series of thiazole derivatives which were 5-acetyl-4-methyl-1,3-thiazole (Series A; T1A-T17A) and 4,5-dimethyl-1,3-thiazole (Series B; T1B-T17B) were synthesized and characterized via 1H and 13C NMR, FTIR, UV-Vis and EI-MS. In IR analysis, all synthesized compounds exhibited important absorption bands. The data of UV analysis confirmed the presence of several chromophores which contributed in formation of electronic transition of π→π* and n→π* in the molecules. All resonances can be observed at expected regions in 1H and 13C NMR analysis. Mass spectra of all compounds showed acceptable m/z values which is in accordance with their theoretical molecular mass. In order to investigate the potential of compounds as antimicrobial agents, screening and in-vitro assays were applied. In disc diffusion test, all compounds in Series A inhibited the tested microbial strains with inhibition zone of 7.0 – 18.5 mm. In Series B, maximum inhibition zone is 16.3 mm. Based on this preliminary screening, ten newly synthesized compounds from Series A which contain substituted phenyl ring at position 2 of thiazole ring which are T3A, T4A, T5A, T7A, T8A, T10A, T11A, T12A, T15A and T16A were selected for further in-vitro assays. The MIC values revealed that all the selected compounds showing remarkable antimicrobial activity against both bacterial strains and fungus with T3A, T4A, T5A and T7A exhibited highest MIC value of 1.25 mg/mL towards B. cereus. The MBC assay indicated that all compounds demonstrating highest mortality properties towards K. pneumoniae with concentration of 10.0 mg/mL. The result of all combinations from synergistic effect between antibiotic and compound showed major antagonism and indifferent effects but a synergistic effect was observed in T4A, T7A, T10A, T11A, T12A and T16A compounds in combination with Tetracycline with FICI values of 0.2-0.3 against E. coli. Compound T4A was the most active compound with significant killing ability towards all tested microbes by showing the lowest number of colonies survived after 30 minutes at range of 13×102 - 43×102 CFU/mL followed by T7A and T5A at range of 17×102 - 48×102 and 13×102 - 51×102 CFU/mL respectively. T4A showed highest percentage of CV uptake towards E. coli and S. flexneri with percentage of 77.7% and 83.1%, respectively. Leakage determination of nucleic acids (UV260) and protein (UV280) absorbing materials showed T4A and T7A showed promising results with highest absorbance values of OD260 were recorded at 1.07 and 0.98 against E. coli while, OD280 were recorded at 1.00 and 0.98 towards B. subtilis at concentration of 4×MIC. All synthesized compounds of both series were subjected to in silico molecular docking screenings towards GlcN-6-P synthase as the target enzyme. The results revealed the significant binding energy values of T4A, T7A and T5A which are in agreement with antimicrobial results with -7.73, -7.32 and -7.31 kcal/mol respectively.