The carbonic anhydrases (CAs) are widely spread metallo-enzymes in all kingdoms of life, from archaea and bacteria, to plants, algae, and animals. There are at least five genetically distinct gene families encoding for these enzymes in organisms all over the phylogenetic tree, whereas in humans 15 different isozymes have been described. Several important physiological and physio-pathological functions are played by the many CA isozymes described so far, related to respiration and transport of CO2/bicarbonate between metabolizing tissues and the lungs, pH and CO2 homeostasis, electrolyte secretion in a variety of tissues/organs, biosynthetic reactions, such as the gluconeogenesis, ureagenesis fatty acid biosynthesis, and tumorigenesis among others (in animals), as well as CO2 fixation (in plants and algae), etc. The presence of these ubiquitous enzymes in so many tissues and in so many different isoforms, represents an attractive goal for the design of inhibitors or activators with biomedical applications. Indeed, some CA inhibitors (CAIs) are clinically used for the treatment or prevention of many diseases/conditions, whereas the applications of the CA activators started to be considered quite recently, mainly for memory therapy, Alzheimer’s disease, etc. The review describes the state of the art in this very dynamic research field, and is structured in such a way as to deal with the mechanism of catalysis, inhibition, X-ray crystallography of the various CA isozymes, alone or in adducts with inhibitors/activators, ending with the drug design of various types of inhibitors, with applications as antiglaucoma drugs, diagnostic tools, antitumor agents, and antiobesity agents, among others. Thus, the high degree of interdisciplinarity may explain why the paper is highly cited by experts in diverse fields involved in CA research.

This is a review article. It presents diverse methodologies useful in the drug design of different pharmacological agents based on CAIs. Indeed, in the past few years this field started to be of great interest for obtaining novel types of antiglaucoma, anticancer, and anti-obesity agents, among others. This was the first thorough review of all these novel applications of CAIs.

Compounds belonging to the CAIs may lead to better drugs useful to treat glaucoma, a chronic eye disease leading to blindness, which is rather diffused, and for which no optimal cure is available at this moment. On the other hand, since several CAs are predominantly found in tumors (and more precisely in hypoxic tumors), compounds of this type seem very promising for discovering novel antitumor therapies. Finally, some CAIs seem to be useful for developing novel anti-obesity drugs. Thus, at least three conditions in need of pharmacological treatment, i.e., glaucoma, cancer, and obesity, may benefit from drugs belonging to this class. It should also be stressed that the isozymes responsible for the three pathologies examined here are different (CA II and IV for glaucoma; CA IX and XII for cancer; CA V for anti-obesity drugs).

My interest in CA research dates back in 1987 when I graduated from the Polytechnic University in Bucharest. I started to collaborate with a Romanian medical doctor who considered that CAIs may be useful for the treatment of gastric ulcers. Although nobody in the international scientific community believed this, in fact Dr. Puscas was right, since in 1999 it has been discovered that Helicobacter pylori, the bacterium responsible for the development of gastric ulcers contains a CA isozyme which is inhibited by sulfonamides (acetazolamide, the most-used drug of this class), and which is essential to the life cycle of the pathogen. Then, after a stay in the USA at the University of Florida, where I collaborated with the most important specialist in the world in this research, Dr. Maren, I established myself at the University of Florence, in Italy, where I and Prof. Andrea Scozzafava started (and in fact continued) several research projects on CA inhibitors and activators. This work led to international recognition, and our laboratory was financed by EU as well as the most important pharmaceutical houses interested in the development of novel therapies based on such compounds. We are currently participating in several such programs, aimed at developing anti-glaucoma, anti-cancer and anti-obesity drugs.