Carbonic anhydrase inhibitors: Design, synthesis and bioevaluation fo new multi-target agents.

Carbonic anhydrases (CAs, EC 4.2.1.1) are a superfamily of ubiquitous metalloenzymes, widely expressed in all kingdoms of life and encoded by eight evolutionarily unrelated gene families: α-, β-, γ-, δ-, ζ-, η-, θ- and ι-CAs. The CAs catalyze the reversible hydration of carbon dioxide into bicarbonate and proton which is physiologically crucial for all living beings, as it is involved in respiration, pH and CO2 homeostasis, transport of CO2/HCO3- and a multitude of biosynthetic reactions. In Homo sapiens, fifteen α-class CA isoforms were identified and characterized. They are implicated in a multitude of physiological processes such as electrolyte secretion in many tissues/organs, metabolic reactions (e.g. gluconeogenesis, lipogenesis, ureagenesis), bone resorption, calcification, and carcinogenesis. Thus, an abnormal expression and/or activity of specific human carbonic anhydrase isoforms (CAs) causes a wide range of human pathological processes that might be addressed through pharmacological interventions involving CA modulation. Moreover, many α-, β-, γ-, η- and ι-CAs were identified in various bacteria, protozoa, and fungi, most of which act as human pathogens. In fact, proper CA isozymes were shown to be crucial for the virulence, growth or acclimatization of those parasites in the hosts. Their inhibition produces growth impairment and defects in the pathogen, being a promising strategy for chemotherapy. The research activity included in this Ph.D. thesis fits in the context of the spreading interest of the scientific community in the carbonic anhydrase field as drug targets for the treatment of a plethora of disorders. Thus, a set of projects involving drug design, synthesis, biological evaluation and in silico investigation of the ligand-target interactions of new CA inhibitors (CAIs) were the main focus of the three-year Ph.D. cycle.