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

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-f...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-11, Vol.55 (22), p.9619-9629
Main Authors: Marini, Anna M, Maresca, Alfonso, Aggarwal, Mayank, Orlandini, Elisabetta, Nencetti, Susanna, Da Settimo, Federico, Salerno, Silvia, Simorini, Francesca, La Motta, Concettina, Taliani, Sabrina, Nuti, Elisa, Scozzafava, Andrea, McKenna, Robert, Rossello, Armando, Supuran, Claudiu T
Format: Article
Language:English
Subjects:
Carbonic Anhydrase Inhibitors - chemistry
Carbonic Anhydrase Inhibitors - pharmacology
Carbonic Anhydrases - chemistry
Catalytic Domain
Crystallography, X-Ray
Humans
Isoenzymes
Models, Molecular
Molecular Structure
Protein Conformation
Pyrazoles - chemistry
Structure-Activity Relationship
Sulfonamides - chemistry
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300878g