Development and In Vivo Evaluation of Fused Benzazole Analogs of Anti-Melanoma Agent HA15

Abstract

Background: In line with our recent discovery of an efficient anticancer thiazolebenzenesulfonamide framework HA15 (1) based on a remarkable endoplasmic reticulum stress inducement mode of action, we report herein a series of innovative constrained HA15 analogs, featuring four types of bicylic derivatives. Results: The structure–activity relationship analysis, using a cell line assay, led us to identify a novel version of HA15: a new benzothiazole derivative (10b) exhibiting important anti-melanoma effect against sensitive and resistant melanoma cells. Meanwhile, compound 10b induced a significant tumor growth inhibition in vivo with no apparent signs of toxicity. Conclusion: These results consistently open new directions to improve and develop more powerful anticancer therapeutics harboring this type of fused framework.

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…[23] The antiproliferative SAR of benzimidazole-sulfonamide hybrids 4 (IC 50 : 1.0 to >50.0 µM, MTT assay) against MGC-803, PC-3, and MCF-7 cancer cell lines illustrated that (1) methyl group at paraposition (R 1 ) was most favorable to the activity and halogen atom at para-position was also tolerated; (2) 3,4,5-trimethoxy group at R 2 position was indispensable for the high activity; (3) replacement of benzimidazole moiety by benzothiophene or phenyl ring reduced the activity. [24,25] Among them, three hybrids 4a-c (IC 50 : 1.0-9.4 µM) F I G U R E 1 Chemical structures of benzimidazole and benzimidazole hybrids were more potent than 5-fluorouracil (IC 50 : 6.8-18.4 µM) against MGC-803, PC-3, and MCF-7 cancer cell lines. In particular, the most active hybrid 4a (IC 50 : 1.0-5.4 µM) not only possessed potent broadspectrum activity against MGC-803, PC-3, MCF-7, HGC27, and SGC-7901 cancer cell lines but also displayed acceptable cytotoxicity (IC 50 : 15.2 µM) towards normal gastric epithelial cell line (GES-1).…”