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

Authors

Hazem Essam Okda, Lingaiah Maram, Mohammad Homaidur Rahman, Andrea Ammara, Simone Giovannuzzi, Dalia Kanaa, Hannah Duggan, Mohamed Elagawany, Lamees Hegazy, Claudiu T Supuran, Bahaa Elgendy

Published in

Journal of medicinal chemistry. Jun 25, 2026. Epub Jun 25, 2026.

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 (K_I = 61.8 nM) and hCA XII (K_I= 40.5 nM), exhibiting over 33- and 51-fold selectivity for these respective isoforms over hCA I (K_I = 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.

PMID:
42350334
Bibliographic data and abstract were imported from PubMed on 26 Jun 2026.

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