Novel sulfonamide-containing dihydropyrimidine derivatives as potent inhibitors of tumor-associated carbonic anhydrase isoforms IX/XII: Design, synthesis, and anticancer evaluation

  • Bioorg Chem. 2026 Oct 10:184:110619. doi: 10.1016/j.bioorg.2026.110619.
Basima A A Saleem  1 ,  Aly M Waseem  2 ,  Kasim Sakran Abass  3 ,  Stefan Bräse  4 ,  Ghallab Alotaibi  5 ,  Abdullah Alkhammash  5 ,  Abdulrahman A Almehizia  6 ,  Ahmed M Naglah  7
Affiliations
  • 1. Department of chemistry, College of Science, University of Mosul, Mosul, Iraq.
  • 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
  • 3. Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Kirkuk, Kirkuk, 36001, Iraq. Electronic address: [email protected].
  • 4. Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, Karlsruhe, 76131, Germany.
  • 5. Department of Pharmacology, College of Pharmacy, Al-Dawadmi Campus, Shaqra University, Shaqra, 11961, Saudi Arabia.
  • 6. Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
  • 7. Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia. Electronic address: [email protected].
PMID: 42896302 DOI: 10.1016/j.bioorg.2026.110619
Abstract

Tumor-associated carbonic anhydrases IX and XII (CA IX and CA XII) are crucial regulators of extracellular acidification in hypoxic Tumors, supporting Cancer cell survival and progression. In this study, a novel series of dihydropyrimidine-sulfonamide hybrids was evaluated for selective inhibition of CA IX and XII and their Anticancer potential. Among them, compound 7b exhibited potent dual inhibition of CA IX (IC₅₀ = 0.025 μM) and CA XII (IC₅₀ = 0.02 μM), with minimal off-target activity against CA I and II. In MTT assays, 7b demonstrated strong antiproliferative activity against HT-29 (IC₅₀ = 0.52 μM), 786-O (IC₅₀ = 0.58 μM), and MCF-7 (IC₅₀ = 0.87 μM) Cancer cell lines, while showing lower cytotoxicity toward WI-38 normal fibroblasts (IC₅₀ = 23.71 μM), yielding selectivity indices of 27.25-45.60 under the present in vitro conditions. Mechanistic studies in HT-29 cells revealed that 7b induces Apoptosis via upregulation of Bax and p53, downregulation of Bcl-2, and activation of Caspase-3 and caspase-9, indicating involvement of the mitochondrial pathway. Molecular docking suggested plausible binding modes for 7b within the CA IX and XII active sites, including predicted Zn2+ coordination and hydrogen-bonding interactions, providing a structural rationale for the experimentally observed inhibitory profile. Taken together, these independent findings demonstrate potent CA IX/XII enzyme inhibition, cellular antiproliferative activity, and apoptosis-associated effects for compound 7b.

Keywords
Antitumor; Apoptosis; Biginelli; Carbonic anhydrase; Sulfonamide.
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