Discovery of Imine-Modified Quinazolinyl Sulfonamides as Dual hCA IX/XII Inhibitors with Potent Antiproliferative Activity

  • J Med Chem. 2026 Jul 9;69(13):16036-16060. doi: 10.1021/acs.jmedchem.6c01358.
Hazem Essam Okda  1  2 ,  Lingaiah Maram  1  2 ,  Mohammad Homaidur Rahman  2  3 ,  Andrea Ammara  4 ,  Simone Giovannuzzi  4 ,  Dalia Kanaa  2  5 ,  Hannah Duggan  2  3 ,  Mohamed Elagawany  2 ,  Lamees Hegazy  1  2  3 ,  Claudiu T Supuran  4 ,  Bahaa Elgendy  1  2
Affiliations
  • 1. Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63110, United States.
  • 2. Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, Missouri 63110, United States.
  • 3. Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, Missouri 63110, United States.
  • 4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, Firenze 50019, Italy.
  • 5. Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt.
PMID: 42350334 DOI: 10.1021/acs.jmedchem.6c01358
Abstract

Tumor-associated carbonic anhydrases (hCA IX and XII) drive Cancer survival under hypoxia. However, developing therapeutics that avoid the ubiquitous physiological isoforms (hCA I and II) to prevent off-target liabilities remains challenging. Herein, we report the design, synthesis, and evaluation of novel 3,4-dihydroquinazoline-based benzenesulfonamides as selective hCA inhibitors. Structure-activity relationship and molecular dynamics studies demonstrated that converting primary amines to imine derivatives successfully abolished hCA I activity while retaining nanomolar potency against hCA IX and XII. Specifically, BE21349 showed high affinity for hCA IX (KI = 61.8 nM) and hCA XII (KI= 40.5 nM), exhibiting over 33- and 51-fold selectivity for these respective isoforms over hCA I (KI = 2090 nM). Antiproliferative screening identified the hCA I-inactive derivatives BE21349 and BE21417 as potent multitarget agents across the NCI-60 panel. Notably, BE21417 exhibited a nearly 6-fold preference for hCA XII over hCA II, representing a promising targeted Anticancer scaffold.

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