Malarial parasite carbonic anhydrase and its inhibitors

Plasmodium falciparum is responsible for the majority of life-threatening cases of human malaria. The global emergence of drug-resistant malarial parasites necessitates identification and characterization of novel drug targets. At present, carbonic anhydrase (CA) genes are identified in limited numbers of protozoa and helminthes parasites, however, they are demonstrated in at least 4 Plasmodium species. The CA gene of P. falciparum encodes an cc-carbonic anhydrase enzyme possessing catalytic properties distinct of that of the human host enzymes. A small library of aromatic sulfonamides, most of which were Schift's bases derived from sulfanilamide/homosulfanilamide/4-aminoethylbenzenesulfonamide and substituted-aromatic aldehydes, or ureido-substituted sulfonamides are good inhibitors of P. falciparum enzyme. The 4-(3,4-dichloroplienylureido-ethyl)-benzenesulfonamide is the most effective antimalarial activity against growth of A falciparum in vitro. The nature of the groups substituting the aromatic-ureido- or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide (i.e., from sulfanilamide to 4-aminoethylbenzenesulfonamide) from which the Schiff's base obtained, are the critical parameters for the CA inhibitory activities of these aromatic sulfonamide derivatives, both against the malarial as well as human enzymes. Thus, the sulfonamide CA inhibitors may have the potential for the development of novel antimalarial drugs.