Carbonic anhydrases (CAs, EC 220.127.116.11) 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.
|Autori:||Marini A; Alfonso Maresca; Mayank Aggarwal; Elisabetta Orlandini; Susanna Nencetti; Federico Da Settimo; Silvia Salerno; Francesca Simorini; Concettina La Motta; Sabrina Taliani; Elisa Nuti; Andrea Scozzafava; Robert McKenna; Armando Rossello; Claudiu T. Supuran.|
|Titolo:||Tricyclic Sulfonamides Incorporating Benzothiopyrano[4,3-c]pyrazole and Pyridothiopyrano[4,3-c]pyrazole Effectively Inhibit a- and ß-Carbonic Anhydrase: X-ray Crystallography and Solution Investigations on 15 Isoforms|
|Anno del prodotto:||2012|
|Digital Object Identifier (DOI):||10.1021/jm300878g ||
|Appare nelle tipologie:||1.1 Articolo in rivista|