The alpha-carbonic anhydrase from the malaria parasite and its inhibition.
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, alpha-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 alpha-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 Schiff's 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 K(i) values in the range of 80 nM-0.50 microM. The 4-(3,4-dichlorophenylureido-ethyl)-benzenesulfonamide is the most effective antimalarial activity against growth of P. falciparum in vitro with an IC(50) of 2 microM. 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 Schiff's 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.
Krungkrai
Jerapan
J
Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand. fmedjkk@md2.md.chula.ac.th
Supuran
Claudiu T
CT
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism*; D008288:Malaria / Q000188:drug therapy / Q000201:enzymology* / Q000469:parasitology*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*
D000962:Antimalarials; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D002256:Carbonic Anhydrases