New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies

Abstract

In this article, a new series of 2-((3,5-disubstituted-2-thioxo-imidazol-1-yl)imino)acenaphthylen-1(2<i>H</i>)-ones were synthesized. Imidazole-2-thione with acenaphthylen-one gave a hybrid scaffold that integrated key structural elements essential for DNA damage <i>via</i> direct DNA intercalation and inhibition of the topoisomerase II enzyme. All the synthesized compounds were screened to detect their DNA damage using a terbium fluorescent probe. Results demonstrated that 4-phenyl-imidazoles <b>5b</b> and <b>5e</b> in addition to 4-(4-chlorophenyl)imidazoles <b>5h</b> and <b>5j</b> would induce detectable potent damage in ctDNA. The four most potent compounds as DNA intercalators were further evaluated for their antiproliferative activity against HepG2, MCF-7 and HCT-116 utilizing the MTT assay. The highest anticancer activity was recorded with compounds <b>5b</b> and <b>5h</b> against the breast cancer cell line MCF-7 which were 1.5- and 3- folds more active than <b>doxorubicin</b>, respectively. Therefore, imidazole-2-thione tethered acenaphthylenone derivatives can be considered as promising scaffold for the development of effective dual DNA intercalators and topoisomerase II inhibitors.