Synthesis and Biological Activity of 2-Benzo[b]thienyl and 2-Bithienyl Amidino-Substituted Benzothiazole and Benzimidazole Derivatives

Novel benzo[b]thienyl- and 2,2 & PRIME;-bithienyl-derived benzothiazoles and benzimidazoles were synthesized to study their antiproliferative and antitrypanosomal activities in vitro. Specifically, we assessed the impact that amidine group substitutions and the type of thiophene backbone have on biological activity. In general, the benzothiazole derivatives were more active than their benzimidazole analogs as both antiproliferative and antitrypanosomal agents. The 2,2 & PRIME;-bithienyl-substituted benzothiazoles with unsubstituted and 2-imidazolinyl amidine showed the most potent antitrypanosomal activity, and the greatest selectivity was observed for the benzimidazole derivatives bearing isopropyl, unsubstituted and 2-imidazolinyl amidine. The 2,2 & PRIME;-bithiophene derivatives showed most selective antiproliferative activity. Whereas the all 2,2 & PRIME;-bithienyl-substituted benzothiazoles were selectively active against lung carcinoma, the benzimidazoles were selective against cervical carcinoma cells. The compounds with an unsubstituted amidine group also produced strong antiproliferative effects. The more pronounced antiproliferative activity of the benzothiazole derivatives was attributed to different cytotoxicity mechanisms. Cell cycle analysis, and DNA binding experiments provide evidence that the benzimidazoles target DNA, whereas the benzothiazoles have a different cellular target because they are localized in the cytoplasm and do not interact with DNA.

Automated summary

Novel benzo[b]thienyl and 2,2'-bithienyl-derived benzothiazoles and benzimidazoles were synthesized and tested for their antiproliferative and antitrypanosomal activities in vitro. The benzothiazole derivatives showed higher activity compared to the benzimidazole analogs. Among them, the 2,2'-bithienyl-substituted benzothiazoles with unsubstituted and 2-imidazolinyl amidine exhibited the most potent antitrypanosomal activity, while the benzimidazole derivatives bearing isopropyl, unsubstituted, and 2-imidazolinyl amidine showed the greatest selectivity. The 2,2'-bithiophene derivatives showed the most selective antiproliferative activity, with the benzothiazoles selectively active against lung carcinoma and the benzimidazoles selectively active against cervical carcinoma cells.