Abstract
The Carbonic Anhydrase (CA, EC 4.2.1.1) activating properties of histamine have been known for a long time. This compound has been extensively modified but only in few instances the imidazole ring has been replaced with other heterocycles. It was envisaged that the imidazoline ring could be a bioisoster of the imidazole moiety. Indeed, we report that clonidine, a 2-aminoimidazoline derivative, was found able to activate several human CA isoforms (hCA I, IV, VA, VII, IX, XII and XIII), with potency in the micromolar range, while it was inactive on hCA II. A series of 2-aminoimidazoline, structurally related to clonidine, was then synthesised and tested on selected hCA isoforms. The compounds were inactive on hCA II while displayed activating properties on hCA I, VA, VII and XIII, with KA values in the micromolar range. Two compounds (10 and 11) showed some preference for the hCA VA or VII isoforms.
Highlights
Carbonic anhydrases (CAs, EC 4.2.1.1) are metallo-enzymes widespread in all life kingdoms
We report that clonidine, a 2-aminoimidazoline derivative, was found able to activate several human CA isoforms, with potency in the micromolar range, while it was inactive on hCA II
Genetic deficiencies of several CA isoforms were reported in the last decades, and in principle a loss of function of these enzymes could be treated with CA selective activators (CAAs)
Summary
Carbonic anhydrases (CAs, EC 4.2.1.1) are metallo-enzymes widespread in all life kingdoms. [11]); these findings point out the need for isoform selective inhibitors or activators to elucidate the role of CA isoforms in cognitive processes. In search for bioisosters of the imidazole moiety, our attention was attracted by the imidazoline ring This feature is present in a well-known drug, Clonidine (CLO, Chart 1), which is clinically used. We decided to measure the potential CA activating properties of this compound, finding that CLO behaves as CAA on several CA isoforms (Table 1). Encouraged by this positive outcome, we synthesised a series of 2-substituted imidazolines (compounds 1–24, Chart 1) and tested their activity on five different hCA isoforms. The ubiquitous cytosolic enzymes CA I and II, the mitochondrial CA VA, which is associated with the glucose homeostasis, the cytosolic CA VII which is abundant in the CNS and has been recently demonstrated to have a protective role against oxidative damage, and the cytosolic CA XIII, which is expressed in the reproductive organs were selected
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