Design, synthesis and pharmacological evaluation of carbonic anhydrase VII and IX inhibitors

Carbonic anhydases (CAs) are ubiquitous enzymes present in human under 15 different isozymes. Each active one catalyzes the hydration reaction of carbon dioxide into bicarbonate anion and proton. Some isozymes contribute to basic physiological processes like among other respiration and acid-base homeostasis while other isozymes are involved in pathologies such as epilepsy (CA VII) and cancer (CA IX). Convulsions observed during epileptic seizures are partly attributed to carbonic anhydrase VII which play a role in neuronal excitation phenomenon. Carbonic anhydrase IX (CA IX) is overexpressed in most cancer tissues and is absent from their normal counterparts. It can acidify the extratumoral medium leading to metastatic behavior. To improve our knowledge on the role of these isozymes, the design of selective CA VII and IX inhibitors is of a great interest. Otherwise, such compounds can potentially be developed as antiepileptic or anticancer agents. A molecular modeling study which combines a direct (homology modelling, docking) and an indirect (pharmacophore, virtual screening) approach of drug design was conducted to create novel and selective inhibitors. In parallel, original indanesulfonamides were designed, synthesized and their inhibitory potencies against the CAs were determined. Docking studies of some derivatives allowed to rationalize the enzymatic data. Then, we evaluated the effect of some indanesulfonamides on a model of cancer cells. The study of the anticonvulsant activity was performed on an in vivo model. Finally, during this work other series of potentially CA inhibitors were also evaluated for their CA inhibitory activities and for one of them for its anticonvulsant effect.