Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors

Bekheit, Mohamed S., Sabry, Eman, Mohamed, Hanan A., Ewies, Ewies F., Kariuki, Benson M. ORCID: https://orcid.org/0000-0002-8658-3897, Fouad, Marwa A., Vullo, Daniela and Supuran, Claudiu T. 2024. Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors. Drug Development Research 85 (1) , e22135. 10.1002/ddr.22135 Item availability restricted.

PDF - Accepted Post-Print Version Restricted to Repository staff only until 23 November 2024 due to copyright restrictions. Download (695kB)

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry
Publisher:	Wiley
ISSN:	0272-4391
Date of First Compliant Deposit:	21 December 2023
Date of Acceptance:	4 November 2023
Last Modified:	05 Feb 2024 16:43
URI:	https://orca.cardiff.ac.uk/id/eprint/165021

Actions (repository staff only)

Edit Item