Synthesis, conformational analysis, and antimalarial activity of tricyclic analogs of artemisinin

Aspects of synthesis, conformational analysis, and antimalarial activity of artemisinin analogs (±)-5-nor-6-desmethyl-4,5-secoartemisinin ( 2), (−)-5-nor-4,5-secoartemisinin ( 3), (+)-4,5-secoartemisinin ( 4), and (+)-4,5-desethano-artemisinin ( 5) 22 are described. The conformations of these multic...

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Published inTetrahedron Vol. 50; no. 4; pp. 957 - 972
Main Authors Avery, Mitchell A, Gao, Fenglan, Chong, Wesley K.M, Hendrickson, Thomas F, Inman, Wayne D, Crews, Phillip
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 24.01.1994
Elsevier
Subjects
Chemistry
Chemistry, Organic
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives
Organic chemistry
Physical Sciences
Preparations and properties
Science & Technology
SYSTEM
HEMIN
AGENTS
1,2,4-TRIOXANES
QINGHAOSU
Antimalarial
Monte Carlo method
Conformational analysis
Overhauser effect
Theoretical study
Lactone
Chiral compound
Tricyclic compound
Oxygen heterocycle
In vitro
Biological activity
Peracetal
Force field method
NMR spectrum
Organic peroxide
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Summary:Aspects of synthesis, conformational analysis, and antimalarial activity of artemisinin analogs (±)-5-nor-6-desmethyl-4,5-secoartemisinin ( 2), (−)-5-nor-4,5-secoartemisinin ( 3), (+)-4,5-secoartemisinin ( 4), and (+)-4,5-desethano-artemisinin ( 5) 22 are described. The conformations of these multicyclic structures were determined through a combination of X-ray crystallography, NMR, and computational analysis, with an emphasis on the 1,2,4-trioxane geometry. Two major solution conformations for both 2 and 3 were found: all chair forms 2a and 3a, and twist-boat/twist-boat/chair forms 2b and 3b, respectively. The major solution conformer 2a matched the solid state structure found via X-ray crystallography. Computations suggest that (+)-4,5-Secoartemisinin ( 4) has three conformations of equal energy: chair/twist-boat, 4a, twist-boat/twist-boat/chair, 4b, corresponding to the X-ray crystal structure, and twist boat/chair/chair, 4c. The 1,2,4-trioxane and lactone rings adopt the twist-boat conformations in 2b, 3b, 4a, and 4c. When compared to artemisinin, these tricyclic, flexible analogs have different geometry yet retain some in vitro antimalarial activity against resistant strains of Plasmodium falciparum. Possible structure/activity correlations are discussed. Graphic
ISSN:0040-4020
1464-5416
DOI:10.1016/S0040-4020(01)80810-3