title: Antiplasmodial activity of quinones: roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase.
abstract: 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.
authors.affiliation: Museum National d'Histoire Naturelle, FRE 3206 CNRS, 61 rue Buffon, Paris Cedex 05, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
authors.forename: Audrone
authors.initials: A
authors.lastname: Maroziene
authors.forename: Henrikas
authors.initials: H
authors.lastname: Nivinskas
authors.forename: Jonas
authors.initials: J
authors.lastname: Sarlauskas
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aliverti
authors.forename: Narimantas
authors.initials: N
authors.lastname: Cenas
mesh_terms: 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
chemical_list: D001388:Aziridines; D004791:Enzyme Inhibitors; D011809:Quinones; C033132:aziridine; D005980:Glutathione Reductase