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Synthesis, Structure, and Antimalarial Activity of Tricyclic 1,2,4‐Trioxanes Related to Artemisinin
Author(s) -
Jefford Charles W.,
Velarde Javier A.,
Bernardinelli Gérald,
Bray Dorothy H.,
Warhurst David C.,
Milhous Wilbur K.
Publication year - 1993
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19930760804
Subject(s) - chemistry , artemisinin , trioxane , pharmacophore , tricyclic , stereochemistry , ether , artemisia annua , sesquiterpene lactone , lactone , plasmodium falciparum , petroleum ether , combinatorial chemistry , sesquiterpene , organic chemistry , malaria , copolymer , immunology , biology , polymer , extraction (chemistry)
Two sets of tricyclic 1,2,4‐trioxanes containing the ABC ( 10 , 11 ) and ACD ring portions ( 21 , 22 , 32 , 33 , 37 , and 38 ) of artemisinin ( 1 ) were synthesized by successive photo‐oxygenation of appropriate enol‐ether precursors to 1,2‐dioxanes and inter‐ and intramolecular reaction with a carbonyl compound or oxo‐substituted side‐chain. The structures of 10 , 21 , and 22 were determined by X‐ray analysis. The anti‐malarial activity of all trioxanes, except 37 and 38 , was evaluated in vitro against chloroquine‐sensitive and chloroquine‐resistant Plasmodium falciparum parasites. Trioxanes 11 and 21 were as active as artemisinin ( 1 ). It was found that neither the lactone function nor rings B and D of 1 were essential for activity. A possible pharmacophore for artemisinin‐like activity, which embodies a spirocyclopentane group attached to C(3) of 1,2,4‐trioxane, was proposed.
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