title: Fluoroartemisinin: trifluoromethyl analogues of artemether and artesunate.
abstract: The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide 8, itself carried out in two steps from artemisinin. The substitution of 8 with methanol, ethanol, or succinic acid allowed the access of C-10 CF(3) analogues of beta-artemether, beta-arteether, or artesunate, respectively, in good yields (up to 89%). The presence of the CF(3) group at C-10 of artemisinin clearly increased the chemical stability under simulated stomach acid conditions. For example, the CF(3) analogue of arteether was found to be around 45 times more stable than arteether itself. The influence of the CF(3) moiety on biological activity was also highlighted. CF(3) analogues of artemether and arteether exhibited a high in vivo antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete clearance of the parasitemia during the entire observation period (25 days).
authors.affiliation: Faculté de Pharmacie, BIOCIS UPRES A 8076 CNRS, 92296 Châtenay-Malabry, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Magueur
authors.forename: Benoit
authors.initials: B
authors.lastname: Crousse
authors.forename: Sébastien
authors.initials: S
authors.lastname: Charneau
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bégué
authors.forename: Danièle
authors.initials: D
authors.lastname: Bonnet-Delpon
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077549:Artemether; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077332:Artesunate; D004355:Drug Stability; D005461:Fluorine; D006868:Hydrolysis; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D005461:Fluorine; D000077332:Artesunate; D000077549:Artemether