Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer
Wagdy M. Eldehna, Alessio Nocentini, Zainab M. Elsayed, Tarfah Al‐Warhi, Nada Aljaeed, Ohoud J. Alotaibi, Mohammad M. Al‐Sanea, Hatem A. Abdel‐Aziz, Claudiu T. Supuran
Abstract
Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (9a–f) or hippuric (11a,b) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker. The target carboxylic acids were evaluated for the potential inhibitory action against hCAs I, II, IX, and XII. Superiorly, benzofuran-containing carboxylic acid derivatives 9b, 9e, and 9f acted as submicromolar hCA IX inhibitors with KIs = 0.91, 0.79, and 0.56 μM, respectively, with selective inhibitory profile against the target hCA IX over the off-target isoforms hCA I and II (SIs: 2 to >63 and 4–47, respectively). Compounds 9b, 9e, and 9f were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. In particular, 9e displayed promising antiproliferative (IC50 = 2.52 ± 0.39 μM), cell cycle disturbance, and pro-apoptotic actions in MDA-MB-231 cells.