Abstract
Using histamine as lead molecule, a library of (hetero)aryl substituted thiazol-2,4-yl derivatives incorporating pyridine as proton shuttling moiety were obtained and investigated as activators of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms I, II, VII and XIV. Some derivatives displayed good activating and selectivity profiles. This study provides an interesting opportunity to study the thiazole scaffold for the design of CA activators (CAAs), possibly acting on the central nervous system and targeting pathologies involving memory and learning impairments.
Highlights
Similar to many enzymes used as therapeutic targets, carbonic anhydrases (CAs, EC 4.2.1.1) are of particular interest considering the large spectra of physiological and pathologic processes in which they are involved
CAAs drug design studies afforded a large number of potent but nonselective CA activators
In order to expand the scope of using thiazole scaffold in the design of CA activators, we present here the synthesis and CA activation studies of a library of derivatives havingaryl substituted thiazol-2,4-yl scaffold and the pyridine group as proton shuttling moiety, which have been investigated on a panel of selected CA isozymes involved in brain function
Summary
Similar to many enzymes used as therapeutic targets, carbonic anhydrases (CAs, EC 4.2.1.1) are of particular interest considering the large spectra of physiological and pathologic processes in which they are involved. Because of their high catalytic activity, the 13 different active carbonic anhydrase isozymes can be modulated or with inhibitors, or with activators. One of the main drawback with the activator of amine and amino-acid types is their lack of selectivity for various CA isoforms Based on this fact, derivatized histamine, substituted histidine and bis-imidazoles compounds were reported as CA activators. In order to expand the scope of using thiazole scaffold in the design of CA activators, we present here the synthesis and CA activation studies of a library of derivatives having (hetero)aryl substituted thiazol-2,4-yl scaffold and the pyridine group as proton shuttling moiety, which have been investigated on a panel of selected CA isozymes involved in brain function
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