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Research Article

Synthesis of 4-sulfamoyl phenyl diazocarboxylic acid derivatives as novel non-classical inhibitors of human carbonic anhydrase II activity: an in vitro study

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Received 16 Aug 2023, Accepted 20 Jan 2024, Published online: 09 Feb 2024
 

Abstract

The first class of carbonic anhydrase inhibitors (CAIs) discovered was sulfonamides, but their clinical use is limited due to side effects caused by their inhibition of multiple CA isoforms. To overcome this, researchers have focused on developing isoform-selective CAIs. This study involved the synthesis and characterization of novel carboxylic acid/sulfonamide derivatives. We investigated the interaction between these compounds and the human carbonic anhydrase II (hCA II) isoform using spectroscopic and computational methods. The synthesized compounds were evaluated based on their IC50, Kd and Ki values, and it was found that the inhibitory potency and binding affinity of the compounds increased with the number of carboxylic acids zinc binding groups. Specifically, the compound C4, with three carboxylic acid groups, showed the strongest inhibitory potency. Fluorescence measurements revealed that all compounds quenched the intrinsic fluorescence of hCA II through a dynamic quenching process, and each compound had one binding site in the hCA II structure. Thermodynamic analysis indicated hydrogen bonds and van der Waals interactions played key roles in the binding of these compounds to hCA II. Docking studies showed that the carboxylic acid groups directly attached to the zinc ion in the active site, displacing water/hydroxide ions and causing steric hindrance. Overall, the strengthening of inhibitory activity and the binding power of these carboxylic acid derivatives for the hCA II makes these compounds interesting for designing novel hCA II inhibitors.

Communicated by Ramaswamy H. Sarma

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

We acknowledge the fiscal assistance of the Kermanshah University of Medical Sciences (KUMS) Research Council (Grant No. 4010608).

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