Heme-dependent radical generation: possible involvement in antimalarial action of non-peroxide microbial metabolites, nanaomycin A and radicicol.
Antimalarial screening was performed for microbial metabolites that simulate artemisinin in their mode of action, a potent antimalarial component of an herbal remedy with a characteristic peroxide structure. Nanaomycin A was identified in this screen as an antimalarial compound, together with radicicol and several other compounds already reported (J. Antibiotics 51: 153 approximately 160, 1998). Nanaomycin A inhibited in vitro growth of the human malaria parasite Plasmodium falciparum with an IC80 value of 33.1 nM. It was as potent as radicicol and about 1/10 as potent as artemisinin. Studies on the mode of action suggested that the antimalarial action of the two non-peroxides, nanaomycin A and radicicol, involved heme-dependent radical generation, as is for the peroxide artemisinin. Namely, the inhibition of in vitro growth of malaria parasite by nanaomycin A or radicicol was reversed by tocopherol, a radical scavenger added to the assay mixture. Secondly, in a reaction system established for radical detection, in which a test radical donor and beta-alanylhistidine as a radical recipient were incubated with and without hemin, the two compounds caused heme-dependent decreases of beta-alanylhistidine, as did artemisinin. Among the 14 microbial metabolites identified during this screening, a correlation was observed between antimalarial activity and heme-dependent radical generating activity.
Tanaka
Y
Y
Research Center for Biological Function, The Kitasato Institute, Tokyo, Japan.
Kamei
K
K
Otoguro
K
K
Omura
S
S
D000818:Animals; D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D037621:Artemisinins; D002336:Carnosine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000302:isolation & purification / Q000494:pharmacology*; D018942:Macrolides; D015394:Molecular Structure; D009285:Naphthoquinones / Q000302:isolation & purification / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000095622:Benzoisochromanequinones
D000962:Antimalarials; D037621:Artemisinins; D002336:Carnosine; D006427:Hemin; D007783:Lactones; D018942:Macrolides; D009285:Naphthoquinones; D012717:Sesquiterpenes; C008638:nanaomycin A; D000095622:Benzoisochromanequinones; C031327:artemisinin; C035359:monorden