title: Structure-activity relationships of the antimalarial agent artemisinin. 1. Synthesis and comparative molecular field analysis of C-9 analogs of artemisinin and 10-deoxoartemisinin.
abstract: A series of C-9 beta-substituted artemisinin analogs (2-21) were synthesized via dianion alkylation of the total synthetic intermediate 57 followed by subsequent ozonolysis/acidification, or by alkylation of the enolate derived from (+)-9-desmethylartemisinin, 2. Inactive acyclic analogs 22 and 23 were synthesized by nucleophilic epoxide opening and the ring contracted analog 24 was prepared by an alternate route. 10-Deoxo-9-alkyl derivatives 68 and 70 were synthesized convergently from intermediates in the preparation of 9-alkyl derivatives. In vitro bioassay was conducted in W-2 and D-6 clones of drug resistant Plasmodium falciparum. Comparative molecular field analysis (CoMFA) of the 9-alkyl lactone derivatives provided a model with a cross-validated r2 = 0.793. Inclusion of inactive 1-deoxyartemisinin analogs 26-42 provided a model with a value of 0.857. The activities of a number of other analogs of divergent structure (43-56) were predicted with good accuracy using the CoMFA model.
authors.affiliation: Department of Chemistry, University of North Dakota, Grand Forks 58202.
authors.forename: M A
authors.initials: MA
authors.lastname: Avery
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: W K
authors.initials: WK
authors.lastname: Chong
authors.forename: S
authors.initials: S
authors.lastname: Mehrotra
authors.forename: W K
authors.initials: WK
authors.lastname: Milhous
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D004351:Drug Resistance; D004563:Electrochemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C063801:deoxoartemisinin; C031327:artemisinin