2. Academic Validation
  3. Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors

Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors

  • Drug Dev Res. 2024 Feb;85(1):e22135. doi: 10.1002/ddr.22135.
Mohamed S Bekheit 1,  Eman Sabry 1,  Hanan A Mohamed 2,  Ewies F Ewies 3,  Benson M Kariuki 4,  Marwa A Fouad 5 6,  Daniela Vullo 7,  Claudiu T Supuran 7
Affiliations

Affiliations

  • 1 Department of Pesticide Chemistry, National Research Centre, Giza, Egypt.
  • 2 Applied Organic Chemistry Department, National Research Centre, Giza, Egypt.
  • 3 Organometallic and Organometalloid Chemistry Department, National Research Centre, Giza, Egypt.
  • 4 School of Chemistry, Cardiff University, Cardiff, UK.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
  • 6 Pharmaceutical Chemistry Department, School of Pharmacy, New Giza University, Cairo, Egypt.
  • 7 NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Chemistry, University of Florence, Florence, Italy.
PMID: 37997034 DOI: 10.1002/ddr.22135
Abstract

The three-components one-pot Kabachnik-Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide-phosphonates (3a-3p) in good to excellent yields (78%-91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X-ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide-phosphonates were evaluated for their inhibitory properties against four isoforms of human Carbonic Anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform.

Keywords

anticancer; carbonic anhydrase inhibitor; one-pot reaction; sulfapyridine; α-aminophosphonate.

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