Antiplasmodial activity of quinones: roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase.
Although quinones have been the subject of great interest as possible antimalarial agents, the mechanism of their antimalarial activity is poorly understood. Flavoenzyme electrontransferase-catalyzed redox cycling of quinones, and their inhibition of the antioxidant flavoenzyme glutathione reductase (GR, EC 1.8.1.7) have been proposed as possible mechanisms. Here, we have examined the activity of a number of quinones, including the novel antitumor agent RH1, against the malaria parasite Plasmodium falciparum strain FcB1 in vitro, their single-electron reduction rates by P. falciparum ferredoxin:NADP(+) reductase (PfFNR, EC 1.18.1.2), and their ability to inhibit P. falciparum GR. The multiparameter statistical analysis of our data implies, that the antiplasmodial activity of fully-substituted quinones (n=15) is relatively independent from their one-electron reduction potential (E(7)(1)). The presence of aziridinyl groups in quinone ring increased their antiplasmodial activity. Since aziridinyl-substituted quinones do not possess enhanced redox cycling activity towards PfFNR, we propose that they could act as as DNA-alkylating agents after their net two-electron reduction into aziridinyl-hydroquinones. We found that under the partial anaerobiosis, i.e., at the oxygen concentration below 40-50 microM, this reaction may be carried out by single-electron transferring flavoenzymes present in P. falciparum, like PfFNR. Another parameter increasing the antiplasmodial activity of fully-substituted quinones is an increase in their potency as P. falciparum GR inhibitors, which was revealed using multiparameter regression analysis. To our knowledge, this is the first quantitative demonstration of a link between the antiplasmodial activity of compounds and GR inhibition.
Grellier
Philippe
P
Museum National d'Histoire Naturelle, FRE 3206 CNRS, 61 rue Buffon, Paris Cedex 05, France.
Maroziene
Audrone
A
Nivinskas
Henrikas
H
Sarlauskas
Jonas
J
Aliverti
Alessandro
A
Cenas
Narimantas
N
D000818:Animals; D001388:Aziridines / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D007700:Kinetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*; D012044:Regression Analysis
D001388:Aziridines; D004791:Enzyme Inhibitors; D011809:Quinones; C033132:aziridine; D005980:Glutathione Reductase