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| - 5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism andMechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials
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| - Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species duringintraerythrocytic life. The most important antioxidative systems are based on the glutathionereductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. Thedevelopment of menadione chemistry has led to the selection of the carboxylic acid 6-[2‘-(3‘-methyl)-1‘,4‘-naphthoquinolyl] hexanoic acid M5 asan inhibitor of the parasitic enzyme. Asreported here, revisiting the mechanism of M5 action revealed an uncompetitive inhibitiontype with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidicfunction of M5 by ester or amide bonds improved antiplasmodial activity. Bioisostericreplacement of the carboxylic function by tetrazole to increase bioavailability and to maintaincomparable acidity led to improved antimalarial properties as well, but only with the cyanoethyl-protected tetrazoles. Using computed ab initio quantum methods, detailed analyses of theelectronic profiles and the molecular properties evidenced the similarity of M5 and the bioisoterictetrazole T4. The potential binding site of these molecules is discussed in light of the recentlysolved crystallographic structure of P. falciparum enzyme.
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