Synthesis, antiproliferative and antitrypanosomal activities, and DNA binding of novel 6-amidino-2-arylbenzothiazoles

Abstract

A series of 6-amidinobenzothiazoles, linked via phenoxymethylene or directly to the 1,2,3-triazole ring with a <i>p</i>-substituted phenyl or benzyl moiety, were synthesised and evaluated <i>in vitro</i> against four human tumour cell lines and the protozoan parasite <i>Trypanosoma brucei</i>. The influence of the type of amidino substituent and phenoxymethylene linker on antiproliferative and antitrypanosomal activities was observed, showing that the imidazoline moiety had a major impact on both activities. Benzothiazole imidazoline <b>14a</b>, which was directly connected to <i>N</i>-1-phenyl-1,2,3-triazole, had the most potent growth-inhibitory effect (IC₅₀ = 0.25 µM) on colorectal adenocarcinoma (SW620), while benzothiazole imidazoline <b>11b</b>, containing a phenoxymethylene linker, exhibited the best antitrypanosomal potency (IC₉₀ = 0.12 µM). DNA binding assays showed a non-covalent interaction of 6-amidinobenzothiazole ligands, indicating both minor groove binding and intercalation modes of DNA interaction. Our findings encourage further development of novel structurally related 6-amidino-2-arylbenzothiazoles to obtain more selective anticancer and anti-HAT agents.