title: Synthesis and antimalarial efficacy of two-carbon-linked, artemisinin-derived trioxane dimers in combination with known antimalarial drugs.
abstract: Malaria continues to be a difficult disease to eradicate largely because of the widespread populations it affects and the resistance that malaria parasites have developed against once very potent therapies. The natural product artemisinin has been a boon for antimalarial chemotherapy, as artemisinin combination therapy (ACT) has become the first line of chemotherapy. Because the threat of resistance is always on the horizon, it is imperative to continually identify new treatments, comprising both advanced analogues of all antimalarial drugs, especially artemisinin, and the exploration of novel combinations, ideally with distinct mechanisms of action. Here we report for the first time the synthesis of a series of two-carbon-linked artemisinin-derived dimers, their unique structural features, and demonstration of their antimalarial efficacy via single oral dose administration in two 60-day survival studies of Plasmodium berghei infected mice. Several of the new endoperoxide chemical entities consistently demonstrated excellent antimalarial efficacy, and combinations with two non-peroxide antimalarial drugs have been studied.
authors: Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland, 21218, USA. bryan.mott@nih.gov
authors: Bryan T
authors: BT
authors: Mott
authors: Abhai
authors: A
authors: Tripathi
authors: Maxime A
authors: MA
authors: Siegler
authors: Cathy D
authors: CD
authors: Moore
authors: David J
authors: DJ
authors: Sullivan
authors: Gary H
authors: GH
authors: Posner
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002244:Carbon / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D019281:Dimerization; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010962:Plasmodium berghei / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D002244:Carbon; C031327:artemisinin