Synthesis, characterization, biological assays and development of new enzyme modulators for the treatment of human pathologies

Carbonic anhydrases (CAs, EC 4.2.1.1) are a family of metalloenzymes widespread in all life kingdoms genetically classified in 7 unrelated classes (i.e. α-, β-, γ-, δ-, ζ-, η- and θ). These enzymes catalyse a very simple and essential physiological reaction, which is the carbon dioxide hydration to afford bicarbonate and protons. So far, 16 different α-CA isoforms were isolated and characterized in mammals. In many tissues CAs are concomitantly present in a variety of isoforms, which differ for their kinetics, structural properties as well as cellular and tissutal abundancy. To date, human (h) CAs are well established therapeutic targets to treat a hypertension, glaucoma. New proof-of-concepts are therapeutic applications for the treatment of epilepsy, obesity related pathologies and neuropathic pain. In the last years CA inhibitors (CAIs) were validated for the treatment of hypoxic tumors. Within the scope of this Thesis, we report new and more isoform selective modulators of CAs expressed in humans and/or in pathogenic organisms with the intent to pave the ways to the treatment of pathologies by means of innovative approaches. The current Thesis is composed of seven chapters, each one dealing with the drug design, synthesis as well as in vitro kinetic assay of new CA modulators: (i) Novel inhibitors against hCAs (ii) Potential anticancer drugs targeting primarily hCA IX and XII that are predominantly expressed in tumor cells. (iii) New class of agents for the prevention of diabetic cerebrovascular pathology (which probably target the mitochondrial isoforms hCA VA and/or hCA VB). (iv) Potential drug leads for the treatment of different neurological disorders such as antiepileptic or neuropathic pain (probably targeting hCA II and VII). (v) Agents that target various CAs from pathogenic microorganisms such as bacteria and protozoa. (vi) New activators of hCAs (vii) Kinetic activation studies on no human expressed CAs such as the α-, β-, γ-, δ-, ζ- and η-classes.