5-substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials.
Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during intraerythrocytic life. The most important antioxidative systems are based on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl] hexanoic acid M(5) as an inhibitor of the parasitic enzyme. As reported here, revisiting the mechanism of M(5) action revealed an uncompetitive inhibition type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic function of M(5) by ester or amide bonds improved antiplasmodial activity. Bioisosteric replacement of the carboxylic function by tetrazole to increase bioavailability and to maintain comparable acidity led to improved antimalarial properties as well, but only with the cyanoethyl-protected tetrazoles. Using computed ab initio quantum methods, detailed analyses of the electronic profiles and the molecular properties evidenced the similarity of M(5) and the bioisoteric tetrazole T(4). The potential binding site of these molecules is discussed in light of the recently solved crystallographic structure of P. falciparum enzyme.
Biot
Christophe
C
Bioinformatique Génomique et Structurale, CP 165/61, Université Libre de Bruxelles, 50 Av. F. D. Roosevelt, B-1050 Brussels, Belgium. christophe.biot@ensc-lille.fr
Bauer
Holger
H
Schirmer
R Heiner
RH
Davioud-Charvet
Elisabeth
E
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002208:Caproates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004351:Drug Resistance; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C494556:6-(2'-(3'-methyl)-1',4'-naphthoquinolyl)hexanoic acid; D000962:Antimalarials; D002208:Caproates; D008024:Ligands; D009285:Naphthoquinones; D011355:Prodrugs; D013777:Tetrazoles; D005980:Glutathione Reductase