Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer

  • ACS Med Chem Lett. 2020 Mar 18;11(5):1022-1027. doi: 10.1021/acsmedchemlett.0c00094.
Wagdy M Eldehna  1  2 ,  Alessio Nocentini  3 ,  Zainab M Elsayed  2 ,  Tarfah Al-Warhi  4 ,  Nada Aljaeed  4 ,  Ohoud J Alotaibi  4 ,  Mohammad M Al-Sanea  5 ,  Hatem A Abdel-Aziz  6 ,  Claudiu T Supuran  3
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 2. Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 4. Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
  • 5. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia.
  • 6. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.
PMID: 32435420 DOI: 10.1021/acsmedchemlett.0c00094
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.