Monothiooxalamide-Benzothiazole Hybrids: Predictive Docking on HDAC6, Synthesis, Molecular Structure, and...

A new family of monothiooxalamide derived from 2-aminobenzothiazole was synthesized with the purpose of investigating its anticancer activity. The design of the compounds was focused on targeting the HDAC6 enzyme, a target for antineoplastic drugs. The in silico affinity of compounds to HDAC6 was performed and confirmed by docking simulation. The structures of monothiooxalamide-benzothiazole hybrids were characterized by 1D and 2D NMR experiments, as well as through mass spectrometry and IR spectroscopy. In addition, the antiproliferative activity of compounds was assessed in human breast cancer cell lines (MCF-7 and MDA-MB231) and non-malignant cells (MCF-10A and NIH/3T3). The most active compound was N-(benzo[d]thiazol-2-yl)-2-((4-methoxybenzyl)amino)-2-thioxoacetamide (1c), which inhibited breast cancer cell growth and invasiveness in vitro and induced late apoptosis in the MCF-7 cell line. The molecular structure of 1c was solved by single-crystal X-ray diffraction. The supramolecular arrangement of benzothiazole and 4-methoxy-benzylamine moieties, present in the crystal structure of 1c, was consistent with the interactions on the docked DD2-HDAC6 catalytic site.