Abstract
A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.
Highlights
N-Heterocycle Derivatives as Carbonic Anhydrases (CAs) are metalloenzymes which catalyze the reversible hydration of carbon dioxide (CO2 ) to bicarbonate (HCO3 − ) and a proton (H+ )
Various therapeutic applications can be envisaged for CarbonicAnhydrase Activators (CAAs), provided these molecules are endowed with isoform selectivity
We showed that 2-amino-imidazolines structurally related to clonidine were able to activate the human Carbonic Anhydrase (hCA) isoform with KA values in the micromolar range, clonidine were able to activate the hCA isoform with KA values in the micromolar range, suggesting that the imidazoline group could be a good bioisostere for the imidazole ring suggesting that the imidazoline group could be a good bioisostere for the imidazole ring for novel types of CAAs [24]
Summary
N-Heterocycle Derivatives as Carbonic Anhydrases (CAs) are metalloenzymes which catalyze the reversible hydration of carbon dioxide (CO2 ) to bicarbonate (HCO3 − ) and a proton (H+ ). This simple reaction is essential for many physiological processes and it is carried out with the assistance of a bivalent ion (Zn2+ in vertebrates) located within the catalytic site of CAs. Human. Small polar molecules, such as amino acids and endogenous or synthetic amines, are able to increase the catalytic turnover of these enzymes [2]. Various therapeutic applications can be envisaged for CAAs, provided these molecules are endowed with isoform selectivity
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