Synthesis, stability, and antimalarial activity of new hydrolytically stable and water-soluble (+)-deoxoartelinic acid.
(+)-Deoxoartelinic acid (13), a new hydrolytically stable, water-soluble, and potent non-acetal-type antimalarial drug candidate, was successfully prepared from artemisinic acid by using sulfur ylide and photooxygenative cyclization in seven steps. This compound showed superior in vitro antimalarial activity against the chloroquine-resistant K1 strain of Plasmodium falciparum and higher suppression (98.7%) than arteether in vivo against Plasmodium chabaudi infected mice. (+)-Deoxoartelinic acid also showed remarkable stability with a half-life of 258.66 h, 23 times more stable than clinically useful arteether in simulated stomach acid, and improved solubility, 4 times more soluble than artemisinin in water.
Jung
Mankil
M
Department of Chemistry, Yonsei University, Seoul 120-749, Korea. mkjung@alchemy.yonsei.ac.jp
Lee
Kyunghoon
K
Kendrick
Howard
H
Robinson
Brian L
BL
Croft
Simon L
SL
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis; D008288:Malaria / Q000401:mortality; D051379:Mice; D010961:Plasmodium / Q000187:drug effects; D012995:Solubility; D013237:Stereoisomerism
D000962:Antimalarials; D006575:Heterocyclic Compounds, 3-Ring; C467717:deoxoartelinic acid; D002738:Chloroquine