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J Med Chem. 2012 Nov 26;55(22):9619-29. doi: 10.1021/jm300878g. Epub 2012 Nov 8.

Tricyclic sulfonamides incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole effectively inhibit α- and β-carbonic anhydrase: X-ray crystallography and solution investigations on 15 isoforms.

Author information

1
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. marini@farm.unipi.it

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.

PMID:
23067387
DOI:
10.1021/jm300878g
[Indexed for MEDLINE]

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