Malarial Parasite Carbonic Anhydrase and Its Inhibitors

Abstract

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 alpha-carbonic anhydrase enzyme possessing catalytic properties distinct of that of the human host enzymes. A small library of aromatic sulfonamides, most of which were Schiff'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-dichlorophenylureido-ethyl)-benzenesulfonamide is the most effective antimalarial activity against growth of P. 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.

Malaria parasite carbonic anhydrase: inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

“…The amino acid sequences of these parasites are not similar to those of the mosquito (Aedes aegypti) and human CA I, II, III and VI isozymes. In silico analyses show the limited information of the putative 毩 -CA genes in all parasite genomes, due in part to the low percentage of amino acid identity among the parasite CAs [24,25].…”

“…In helminthes, the CA genes are identified in a parasitic nematode Ascaris suum (having only one putative gene), a free-living nematode Caenorhabditis elegans (containing six putative genes), and a filarial nematode Brugia malayi (having seven putative genes) [24][25][26] . The deduced amino acid sequences of these parasitic enzymes share very low identity among themselves.…”

“…The deduced amino acid sequences of these parasitic enzymes share very low identity among themselves. The Ascaris CA has the highest identity to the mosquito and human CA III (31%-32%), whereas the Caenorhabditis CA has only 25% identity to the human CA II and III [24,25].…”

“…Nevertheless, the malarial CA sequence is closely related to the Theileria enzyme, and is distinct from the other protozoan enzymes. The predicted protein sequences of the malaria parasites, however, exhibit high amino acid identity among themselves, including P. falciparum, Plasmodium chabaudi(P. chabaudi), Plasmodium yoelii(P. yoelii), and Plasmodium berghei(P. berghei) [24,25] .…”

“…CA was first purified from bovine red cells in 1933 [12] , followed by the identification of several isozymes ubiquitously distributed in all organisms so far examined [13][14][15][16][17][18][19] . The CAs in protozoa and helminthes parasites are found sparsely [24][25][26][27][28] . Recent studies on the biochemistry and the crystal structure of CAs from various organisms reveal that they evolved independently al least five times, with five genetically distinct enzyme families known to date: the 毩 -, 毬 -, 毭 -, 毮 -, and 毱 -CAs [29][30][31][32] .…”