1. Synthesis, antiproliferative and antitrypanosomal activities, and DNA binding of novel 6-amidino-2-arylbenzothiazoles.
- Author
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Racané L, Rep V, Kraljević Pavelić S, Grbčić P, Zonjić I, Radić Stojković M, Taylor MC, Kelly JM, and Raić-Malić S
- Subjects
- Amidines chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Antiprotozoal Agents pharmacology, Benzothiazoles pharmacology, Cell Proliferation drug effects, Colorectal Neoplasms drug therapy, DNA chemistry, Drug Evaluation, Preclinical, Humans, Imidazolines chemistry, Intercalating Agents pharmacology, Nucleic Acid Conformation, Structure-Activity Relationship, Triazoles chemistry, Antiprotozoal Agents chemical synthesis, Benzothiazoles chemical synthesis, Intercalating Agents chemical synthesis, Trypanosoma brucei brucei drug effects
- Abstract
A series of 6-amidinobenzothiazoles, linked via phenoxymethylene or directly to the 1,2,3-triazole ring with a p -substituted phenyl or benzyl moiety, were synthesised and evaluated in vitro against four human tumour cell lines and the protozoan parasite Trypanosoma brucei . 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 14a , which was directly connected to N -1-phenyl-1,2,3-triazole, had the most potent growth-inhibitory effect (IC
50 = 0.25 µM) on colorectal adenocarcinoma (SW620), while benzothiazole imidazoline 11b , 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.- Published
- 2021
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