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

Hazem Essam Okda1,2, Lingaiah Maram1,2, Mohammad Homaidur Rahman2,3

  • 1Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63110, United States.

Journal of Medicinal Chemistry
|June 25, 2026
PubMed

Insights

Novel benzenesulfonamides selectively inhibit tumor-associated carbonic anhydrases (hCA IX and XII) while sparing physiological isoforms (hCA I and II). This targeted approach yields potent anticancer agents with reduced off-target effects.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Enzyme Inhibition

Background:

  • Tumor-associated carbonic anhydrases (hCA IX and XII) are crucial for cancer survival, particularly under hypoxic conditions.
  • Developing selective inhibitors targeting hCA IX and XII while avoiding ubiquitous physiological isoforms (hCA I and II) is essential to minimize off-target liabilities.

Purpose of the Study:

  • To design, synthesize, and evaluate novel 3,4-dihydroquinazoline-based benzenesulfonamides as selective inhibitors of tumor-associated carbonic anhydrases.
  • To investigate the structure-activity relationships and molecular dynamics of these novel compounds.
  • To assess the antiproliferative activity of promising candidates against cancer cell lines.

Main Methods:

  • Synthesis of novel 3,4-dihydroquinazoline-based benzenesulfonamides.
  • Structure-activity relationship (SAR) studies to optimize inhibitor selectivity.
  • Molecular dynamics simulations to understand binding interactions.
  • Enzyme inhibition assays to determine binding affinities (KI) for various carbonic anhydrase isoforms.
  • Antiproliferative screening using the NCI-60 cancer cell line panel.

Main Results:

  • Imine derivatives of benzenesulfonamides effectively abolished hCA I activity.
  • Compounds retained nanomolar potency against hCA IX and hCA XII.
  • BE21349 demonstrated high affinity for hCA IX (KI = 61.8 nM) and hCA XII (KI = 40.5 nM), with significant selectivity over hCA I (>33-fold and >51-fold, respectively).
  • BE21349 and BE21417, inactive against hCA I, showed potent multitarget antiproliferative activity across the NCI-60 panel.
  • BE21417 exhibited a ~6-fold preference for hCA XII over hCA II.

Conclusions:

  • Novel 3,4-dihydroquinazoline-based benzenesulfonamides represent a promising class of selective carbonic anhydrase inhibitors.
  • These compounds demonstrate potential as targeted anticancer agents due to their potent activity against hCA IX and XII and reduced inhibition of hCA I and II.
  • BE21349 and BE21417 warrant further investigation as therapeutic scaffolds for cancer treatment.

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