Identification of Potent and Selective Human Carbonic Anhydrase VII (hCA VII) Inhibitors

Carbonic anhydrases (CA, EC 4.2.1.1) are a family of metalloenzymes comprising different isoforms with different tissue and cellular localization. They play an important role in many physiological processes linked to the catalytic hydration of carbon dioxide to bicarbonate, regulating respiration, pH, electrolyte secretion, biosynthetic reactions, bone resorption, calcification, etc. Furthermore, these enzymes are involved in several pathological pathways, suggesting the development of carbonic-anhydrase inhibitors (CAIs) as new tools, such as diuretics, anticonvulsants, antiobesity and antitumor drugs. In this paper two distinct classes of carbonic anhydrase inhibitors have been designed, synthesized and evaluated against some physiologically relevant mammalian isoforms. The biological results showed that some of the studied compounds are potent and selective hCA VII inhibitors. They also showed Ki values similar to other known CAIs already in clinical use. Moreover, they behave as some of the most selective hCA VII inhibitors reported to date. Notably, the Ki values against hCA II and hCA VII differ by four and two order of magnitude, respectively, for the two most representative compounds 8 and 13, suggesting that these compounds might be considered as lead structures for the identification of new neuroprotective agents that selectively target hCA VII.