Novel amidino substituted benzimidazole and benzothiazole benzo[b]thieno-2-carboxamides exert strong antiproliferative and DNA binding properties

• Published in: European journal of medicinal chemistry 2017-08, Vol.136, p.468-479
• Main Authors: Cindrić, Maja, Jambon, Samy, Harej, Anja, Depauw, Sabine, David-Cordonnier, Marie-Hélène, Kraljević Pavelić, Sandra, Karminski-Zamola, Grace, Hranjec, Marijana
• Format: Article
• Language: English
• Subjects: Amidines; Amidines - chemistry; Amidines - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Benzimidazoles; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; benzo[b]thieno-2-carboxamides; Benzothiazoles; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Binding Sites - drug effects; Cell Proliferation - drug effects; DNA binding; DNA, Neoplasm - chemistry; DNA, Neoplasm - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Topoisomerase poisoning; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.05.014

Within this manuscript design, synthesis of novel 2-imidazolinyl substituted benzo[b]thieno-2-carboxamides bearing either benzimidazole or benzothiazole subunit and biological activity are presented and described. The antiproliferative activities were assessed in vitro on a panel of human cancer cell lines. Tested compounds showed moderate activity while cytotoxicity on normal fibroblasts was lower in comparison with 5-fluorouracile. The variations of 2-imidazolinyl substituent at heteroaromatic subunits in different positions led to different cytotoxic properties. The strongest selective activity against HeLa cells was observed for the benzothiazole derivative 4d with 2-imidazolinyl group at the benzo[b]thiophene subunit with a corresponding IC50 = 1.16 μM. Additionally, several biological experiments were performed to explain the mode of biological action. Fluorescence microscopy evidenced nuclear subcellular localization of compounds 3a, 4a and 4c. Additionally, detailed DNA binding studies confirmed a strong DNA groove binding for derivatives 4a and 4c while DNase I footprinting experiments evidenced sequence-selective binding of compound 4c in the A-T rich side. Furthermore, topoisomerase suppressive effect was for compounds 4a-4c. [Display omitted] •Synthesis of 2-imidazolinyl substituted benzo[b]thiophene-2-carboxamides.•Novel derivatives with either benzimidazole/benzothiazole subunit.•Potent anti-cancer agents.•DNA binding studies confirmed a strong DNA groove binding.•Noticed sequence-selective binding in the A-T rich side.