Tricyclic Sulfonamides
Incorporating Benzothiopyrano[4,3‑<i>c</i>]pyrazole
and Pyridothiopyrano[4,3‑<i>c</i>]pyrazole Effectively Inhibit α- and β‑Carbonic Anhydrase: X‑ray Crystallography and Solution Investigations on 15 Isoforms
- Publication date
- Publisher
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 <b>3a</b>–<b>e</b> were designed as constrained analogues
of celecoxib and valdecoxib. The most interesting feature of sulfonamides <b>3</b> 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