The Alpha-Carbonic Anhydrase from the Malaria Parasite and its Inhibition

Jerapan      Krungkrai; Claudiu   T.   Supuran

doi:10.2174/138161208783877901

Abstract

Plasmodium falciparum is the protozoan parasite responsible for the majority of life-threatening cases of human malaria, causing more than one million deaths a year. The global emergence of drug-resistant malarial parasites necessitates identification and characterization of novel drug targets. At present, α-carbonic anhydrase (CA) genes are identified in limited numbers of parasites in both protozoa and helminthes, however, the malarial genes are found in four species of Plasmodium. The CA gene of P. falciparum encodes an α- carbonic anhydrase enzyme possessing catalytic properties distinct of that of the human host CA I and II isozymes. P. falciparum native and recombinant enzymes have been prepared. A library of aromatic sulfonamides, most of which were Schiffs bases derived from sulfanilamide/ homosulfanilamide/4-aminoethyl-benzenesulfonamide and substituted-aromatic aldehydes, or ureido-substituted sulfonamides are very good inhibitors for P. falciparum enzyme with Ki values in the range of 80 nM – 0.50 μM. The 4-(3,4-dichlorophenylureidoethyl)- benzenesulfonamide is the most effective antimalarial activity against growth of P. falciparum in vitro with an IC50 of 2 μM. The structure 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 Schiffs base obtained, are the critical parameters for the enzyme inhibitory activities of these aromatic sulfonamide derivatives, both against the malarial as well as human enzymes. This review provides further support that the CA may have essential roles in the parasite metabolism. Thus, the aromatic sulfonamide CA inhibitors may have potential for development of novel antimalarial drugs.

Keywords: helminthes, protozoa, malaria parasite, drug design, antimalarial agents, aromatic sulfonamides, carbonic anhydrase inhibitor, Alpha-carbonic anhydrase