Carbonic anhydrase inhibitors. Inhibition of Plasmodium falciparum carbonic anhydrase with aromatic sulfonamides: towards antimalarials with a novel mechanism of action?

The malarial parasite Plasmodium falciparum encodes for an alpha-carbonic anhydrase (CA) enzyme possessing catalytic properties distinct of that of the human host, which was only recently purified. A series of aromatic sulfonamides, most of which were Schiff's bases derived from sulfanilamide/homosulfanilamide/4-aminoethylbenzenesulfonamide and substituted-aromatic aldehydes, or ureido-substituted such sulfonamides, were investigated for in vitro inhibition of the malarial parasite enzyme (pfCA) and the growth of P. falciparum. Several inhibitors with affinity in the micromolar range (K(I)'s in the range of 0.080-1.230 microM) were detected, whereas the most potent such derivatives were the clinically used sulfonamide CA inhibitor acetazolamide, and 4-(3,4-dichlorophenyl-ureidoethyl)-benzenesulfonamide, which showed an inhibition constant of 80 nM against pfCA, being four times more effective an inhibitor as compared to acetazolamide (K(I) of 315 nM). The lipophilic 4-(3,4-dichlorophenylureido-ethyl)-benzenesulfonamide was also an effective in vitro inhibitor for the growth of P. falciparum (IC50 of 2 microM), whereas acetazolamide achieved the same level of inhibition at 20 microM. This is the first study proving that antimalarials possessing a novel mechanism of action can be obtained, by inhibiting a critical enzyme for the life cycle of the parasite. Indeed, by inhibiting pfCA, the synthesis of pyrimidines mediated by carbamoylphosphate synthase is impaired in P. falciparum but not in the human host. Sulfonamide CA inhibitors have the potential for the development of novel antimalarial drugs.