The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase.
Various aza-analogues of 1,4-naphthoquinone and menadione were prepared and tested as inhibitors and substrates of the plasmodial thioredoxin and glutathione reductases as well as the human glutathione reductase. The replacement of one to two carbons at the phenyl ring of the 1,4-naphthoquinone core by one to two nitrogen atoms led to an increased oxidant character of the molecules in accordance with both the redox potential values and the substrate efficiencies. Compared to the 1,4-naphthoquinone and menadione, the quinoline-5,8-dione 1 and both quinoxaline-5,8-diones 5 and 6 behaved as the most efficient subversive substrates of the three NADPH-dependent disulfide reductases tested. Modulation of these parameters was observed by alkylation of the aza-naphthoquinone core.
Morin
Christophe
C
Université Joseph Fourier, Département de Chimie Moléculaire, CNRS UMR-5250, ICMG FR-2607, Grenoble Cedex 9, France.
Besset
Tatiana
T
Moutet
Jean-Claude
JC
Fayolle
Martine
M
Brückner
Margit
M
Limosin
Danièle
D
Becker
Katja
K
Davioud-Charvet
Elisabeth
E
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004563:Electrochemistry; D004912:Erythrocytes / Q000201:enzymology*; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D001372:Aza Compounds; D009285:Naphthoquinones; D013879:Thioredoxins; D005980:Glutathione Reductase; C035342:1,4-naphthoquinone