title: A partial convergence in action of methylene blue and artemisinins: antagonism with chloroquine, a reversal with verapamil, and an insight into the antimalarial activity of chloroquine.
abstract: Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).
authors: Department of Chemistry, Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China. haynes@ust.hk
authors: Richard K
authors: RK
authors: Haynes
authors: Kwan-Wing
authors: KW
authors: Cheu
authors: Ka-Yan
authors: KY
authors: Li
authors: Maggie Mei-Ki
authors: MM
authors: Tang
authors: Ho-Ning
authors: HN
authors: Wong
authors: Min-Jiao
authors: MJ
authors: Chen
authors: Zu-Feng
authors: ZF
authors: Guo
authors: Zhi-Hong
authors: ZH
authors: Guo
authors: Paolo
authors: P
authors: Coghi
authors: Diego
authors: D
authors: Monti
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008751:Methylene Blue / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D005182:Flavin-Adenine Dinucleotide; D002738:Chloroquine; D014700:Verapamil; D008751:Methylene Blue