Synthesis, Biological Evaluation, and Interaction with Calf Thymus-DNA of Mono- and Diamidino-Substituted Imidazo[4,5-b]pyridines.

A series of cyano- and amidino-substituted derivatives of N3-methyl-imidazo[4,5-b]pyridines is designed and synthesized to investigate their biological activity. The previously published synthetic methods for the synthesis of targeted derivatives are further optimized to obtain higher yields. In order to investigate how the number, the position, and the type of amidine groups affect biological activity, targeted compounds are substituted with amidine groups on opposite sides of molecules. All compounds demonstrated moderate to strong antiproliferative activity in vitro against tested cancer cell lines with good selectivity against HeLa cancer cell lines. 6-Benzonitril-substituted compound 12 showed pronounced antiproliferative activity against HeLa (IC50 0.7 µM) and MCF7 (IC50 0.6 µM) cancer cell lines. Compound 19 bearing two imidazolinyl amidine groups also showed selective activity against MCF7 (IC50 0.6 µM) cancer cell line. Spectroscopic investigation of the interaction of the most active derivatives with calf thymus-DNA is monitored by UV/Vis, emission, and circular dichroism spectroscopy. The lead compound 19 is shown to bind in the minor groove of DNA, suggesting a possible mechanism of action in tumor cells. The compounds are also tested for their antibacterial activity in vitro, but they showed no antibacterial activity against the tested bacterial strains.