Structure-activity relationships of the antimalarial agent artemisinin. 7. Direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates

Mitchell A. Avery, Maria Alvim-Gaston, Jeffrey A. Vroman, Baogen Wu, Arba L Ager, Wallace Peters, Brian L. Robinson, William Charman

Research output: Contribution to journalArticle

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Abstract

On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9β-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed a one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF3-etherate/Et3SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity. Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.

Original languageEnglish (US)
Pages (from-to)4321-4335
Number of pages15
JournalJournal of Medicinal Chemistry
Volume45
Issue number19
DOIs
StatePublished - Sep 12 2002

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Antimalarials
Lactones
Structure-Activity Relationship
Screening
Plasmodium yoelii
Pyrans
Plasmodium berghei
Halogens
Acids
Pharmacokinetics
Oxygenation
Quantitative Structure-Activity Relationship
Bioassay
Plasmodium falciparum
Selenium
Biological Products
Biological Assay
Toxicity
Clone Cells
artemisinine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structure-activity relationships of the antimalarial agent artemisinin. 7. Direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates. / Avery, Mitchell A.; Alvim-Gaston, Maria; Vroman, Jeffrey A.; Wu, Baogen; Ager, Arba L; Peters, Wallace; Robinson, Brian L.; Charman, William.

In: Journal of Medicinal Chemistry, Vol. 45, No. 19, 12.09.2002, p. 4321-4335.

Research output: Contribution to journalArticle

Avery, Mitchell A. ; Alvim-Gaston, Maria ; Vroman, Jeffrey A. ; Wu, Baogen ; Ager, Arba L ; Peters, Wallace ; Robinson, Brian L. ; Charman, William. / Structure-activity relationships of the antimalarial agent artemisinin. 7. Direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 19. pp. 4321-4335.
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