Lead Development of Thiazolyl­sulfonamides with Carbonic Anhydrase Inhibitory Action

A series
of congeners structurally related to pritelivir, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)­phenyl]­acetamide,
a helicase-primase inhibitor for the treatment of herpes simplex virus
infections, was prepared. The synthesized primary and secondary sulfonamides
were investigated as inhibitors of six physiologically and pharmacologically
relevant human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms,
the cytosolic enzymes hCA I and II, the mitochondrial ones hCA VA
and VB, and the transmembrane, tumor associated hCA IX and XII. Low
nanomolar inhibition KI values were detected
for all of them, with a very interesting and well-defined structure–activity
relationship. As many CAs are involved in serious pathologies, among
which are cancer, obesity, epilepsy, glaucoma, etc., sulfonamide inhibitors
as those reported here may be of interest as drug candidates. Furthermore,
pritelivir itself is an effective inhibitor of some CAs, also inhibiting
whole blood enzymes from several mammalian species, which may be a
favorable pharmacokinetic feature of the drug which can be transported
throughout the body bound to blood CA I and II.