AI Article Synopsis
- Carbonic anhydrases (CAs) are important enzymes involved in various physiological and pathological processes, making them key targets for drug development.
- Researchers have introduced a new class of CA inhibitors that utilize a thiopyrano-fused pyrazole structure with a 4-sulfamoylphenyl attachment, modeled after celecoxib and valdecoxib.
- The new sulfonamides show strong inhibition against specific human carbonic anhydrases and mycobacterial enzymes, while displaying significantly weaker inhibition against other human CAs, with their distinct inhibition profiles explained through structural studies.
Article Abstract
Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.
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