Synthesis and Evaluation of Imidazole Derivatives Bearing Imidazo[2,1-b] [1,3,4]thiadiazole Moiety as Antibacterial Agents.

Background: Drug-resistant infections kill hundreds of thousands of people globally every year. In previous work, we found that tri-methoxy- and pyridine-substituted imidazoles show strong antibacterial activities.

Objective: The aim of this work was to investigate the antibacterial activities and bacterial resistances of imidazoles bearing an aromatic heterocyclic, alkoxy, or polycyclic moiety on the central ring.

Methods: Three series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4- yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles (13a-e, 14a-d, and 15a-f) were synthesized and their antibacterial activity was evaluated. The structures were confirmed by their ¹H NMR, ¹³C NMR, and HRMS spectra. All the synthesized compounds were screened against Gram-positive, Gramnegative, and multidrug-resistant bacterial strains.

Results: More than half of the compounds showed moderate or strong antibacterial activity. Among them, compound 13e (MICs = 1-4 μg/mL) showed the strongest activity against Gram-positive and drug-resistant bacteria as well as high selectivity against Gram-negative bacteria. Furthermore, it showed no cytotoxicity against HepG2 cells, even at 100 μM, and no hemolysis at 20 μM.

Conclusion: These results indicate that compound 13e is excellent candicate for further study as a potential antibacterial agent.