title: Preparation of N-sulfonyl- and N-carbonyl-11-azaartemisinins with greatly enhanced thermal stabilities: in vitro antimalarial activities.
abstract: As the clinically used artemisinins do not withstand the thermal stress testing required to evaluate shelf life for storage in tropical countries where malaria is prevalent, there is a need to develop thermally more robust artemisinin derivatives. Herein we describe the attachment of electron-withdrawing arene- and alkanesulfonyl and -carbonyl groups to the nitrogen atom of the readily accessible Ziffer 11-azaartemisinin to provide the corresponding N-sulfonyl- and -carbonylazaartemisinins. Two acylurea analogues were also prepared by treatment of the 11-azaartemisinin with arylisocyanates. Several of the N-sulfonylazaartemisinins have melting points above 200 degrees C and possess substantially greater thermal stabilities than the artemisinins in current clinical use, with the antimalarial activities of several of the arylsulfonyl derivatives being similar to that of artesunate against the drug-sensitive 3D7 clone of the NF54 isolate and the multidrug-resistant K1 strain of P. falciparum. The compounds possess relatively low cytotoxicities. The carbonyl derivatives are less crystalline than the N-sulfonyl derivatives, but are generally more active as antimalarials. The N-nitroarylcarbonyl and arylurea derivatives possess sub-ng ml(-1) activities. Although several of the azaartemisinins possess log P values below 3.5, the compounds have poor aqueous solubility (<1 mg L(-1) at pH 7). The greatly enhanced thermal stability of our artemisinins suggests that strategic incorporation of electron-withdrawing polar groups into both new artemisinin derivatives and totally synthetic trioxanes or trioxolanes may assist in the generation of practical new antimalarial drugs which will be stable to storage conditions in the field, while retaining favorable physicochemical properties.
authors.affiliation: Department of Chemistry, Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China. haynes@ust.hk
authors.forename: Richard K
authors.initials: RK
authors.lastname: Haynes
authors.forename: Ho-Ning
authors.initials: HN
authors.lastname: Wong
authors.forename: Kin-Wo
authors.initials: KW
authors.lastname: Lee
authors.forename: Chung-Man
authors.initials: CM
authors.lastname: Lung
authors.forename: Lai Yung
authors.initials: LY
authors.lastname: Shek
authors.forename: Ian D
authors.initials: ID
authors.lastname: Williams
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Lauren
authors.initials: L
authors.lastname: Rattray
authors.forename: Lindsay
authors.initials: L
authors.lastname: Stewart
authors.forename: Vincent K W
authors.initials: VK
authors.lastname: Wong
authors.forename: Ben C B
authors.initials: BC
authors.lastname: Ko
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D004356:Drug Storage; D006358:Hot Temperature; D012995:Solubility
chemical_list: D000962:Antimalarials; D037621:Artemisinins