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Synthesis, antiproliferative and antitrypanosomal activities, and DNA binding of novel 6-amidino-2-arylbenzothiazoles
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2021-08-30 , DOI: 10.1080/14756366.2021.1959572
Livio Racané 1 , Valentina Rep 2 , Sandra Kraljević Pavelić 3 , Petra Grbčić 3 , Iva Zonjić 4 , Marijana Radić Stojković 4 , Martin C Taylor 5 , John M Kelly 5 , Silvana Raić-Malić 2
Affiliation  

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 (IC50 = 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.



中文翻译:

新型 6-脒基-2-芳基苯并噻唑的合成、抗增殖和抗锥虫活性以及 DNA 结合

摘要

合成了一系列 6-脒基苯并噻唑,通过苯氧基亚甲基连接或直接连接到具有对位取代苯基或苄基部分的 1,2,3-三唑环,并在体外针对四种人类肿瘤细胞系和原生动物寄生虫布氏锥虫进行了评估. 观察到脒基取代基和苯氧基亚甲基接头的类型对抗增殖和抗锥虫活性的影响,表明咪唑啉部分对这两种活性都有重大影响。与N -1-苯基-1,2,3-三唑直接相连的苯并噻唑咪唑啉14a具有最有效的生长抑制作用 (IC 50= 0.25 µM) 在结直肠腺癌 (SW620) 上,而含有苯氧基亚甲基接头的苯并噻唑咪唑啉11b表现出最佳的抗锥虫效力 (IC 90 = 0.12 µM)。DNA 结合测定显示 6-脒基苯并噻唑配体的非共价相互作用,表明 DNA 相互作用的小沟结合和嵌入模式。我们的发现鼓励进一步开发新型结构相关的 6-脒基-2-芳基苯并噻唑,以获得更具选择性的抗癌和抗 HAT 药物。

更新日期:2021-08-30
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