η-Class Carbonic Anhydrases as Antiplasmodial Drug Targets: Current State of the Art and Hurdles to Develop New Antimalarials

Plasmodium falciparum is responsible for the most severe and life-threatening form of malaria. The exceptionally high impact of malaria on human health is related to the ability of the parasites responsible for this disease to modify their genome to evade the human immune system and resist drug therapies. The lack of efficient treatments and acquired resistance to the existing therapies has stimulated efforts to identify new therapeutic targets to fight malaria. P. falciparum, during its exponential growth and replication in the erythrocytes, needs purines and pyrimidines for DNA/RNA synthesis, which are de novo synthesized from HCO3−, ATP, and glutamine. HCO3− is involved in the Plasmodia pyrimidine pathway and is generated from CO2 through the action of metalloenzymes known as carbonic anhydrases (CAs). We will review the current state of the art for inhibiting the CA (PfCAdom) from Plasmodium falciparum using the classical CA inhibitors, such as sulfonamides and their bioisosteres, organic anions, as well as phenol compounds. Some of these showed effective nanomolar inhibitory effect for PfCAdom and could be considered as leads for finding new drug candidates possessing a different mechanism of action from the clinically used drugs to which a considerable degree of drug resistance has been reported.