Synthesis of Hydrazidoureidobenzensulfonamides Incorporating a Nicotinoyl Tail and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity

TL;DR

Scientists created new compounds that effectively inhibit a specific carbonic anhydrase linked to cancer, showing potential for drug development.

Contribution

A novel series of benzenesulfonamides with a hydrazinocarbonyl-ureido linker and 6-arylpyridine tail was synthesized and tested for CA inhibition.

Findings

Some compounds showed strong inhibition of tumor-related CA XII over CA I and II.

Selected compounds displayed favorable drug-like properties in ADME predictions.

Molecular docking revealed insights into the binding mode of these compounds to hCA isoforms.

Abstract

Background: Carbonic anhydrases (CAs) are known to play important roles in several physiological and pathological processes; among them, CAs IX and XII are of particular relevance in cancer therapy due to their involvement in tumor growth and progression. Methods: In this study, a novel series of benzenesulfonamides incorporating a hydrazinocarbonyl-ureido linker alongside a 6-arylpyridine tail was synthesized and evaluated for inhibitory activity through a stopped-flow CO2 hydrase assay on four hCA isoforms. Results: Some of the new compounds exhibited great activity and selectivity toward the tumor-expressed CA XII isoform over the off-target isoforms CA I and CA II. Based on these results, they were selected for ADME prediction studies, showing favorable drug-like properties. To further investigate their binding mode, these compounds were docked into the four hCA isoforms. Conclusions: Overall, the results underscore the potential of compounds bearing a 6-arylpyridine tail along with a hydrazinocarbonyl-ureido linker as a foundation for further inhibitor development.

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