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À propos de : Antimalarial Activity of New Dihydroartemisinin Derivatives. 7.4-(p-Substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyricAcids1-6        

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  • Antimalarial Activity of New Dihydroartemisinin Derivatives. 7.4-(p-Substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyricAcids1-6
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  • To search for water soluble dihydroartemisinin derivatives withhigher efficacy and longerplasma half-life than artesunic or artelinic acid, a series of newstereoisomers of 4-(p-substitutedphenyl)-4(R or S)-[10(α orβ)-dihydroartemisininoxy]butyric acids were synthesized asnewpotential antimalarial agents. Two approaches were taken in thedesign of these new moleculesin an attempt to (a) increase the lipophilicity of the molecule and (b)decrease the rate ofoxidative dealkylation of the target compounds. The new compoundsshowed a 2−10-foldincrease in in vitro antimalarial activity against D-6 andW-2 clones of Plasmodium falciparumthan artemisinin or artelinic acid. R-diastereomersare, in general, more potent than thecorresponding S-diastereomers.p-Chlorophenyl and p-bromophenyl derivativesshowed in vivooral antimalarial activity against P. berghei (with 3/8cured) superior to that of artelinic acid(1/8 cured), whereas p-fluorophenyl andp-methoxyphenyl analogs demonstrated activityonlycomparable (1/8 cured) to that of artelinic acid at the same dosagelevel (64 mg/kg twice aday). The in vivo antimalarial activity of these newcompounds correlates with their SD50(50% parasitemia suppression dose). The biological resultssuggested that an electronic effect,besides the lipophylicity, may play a role in determining the efficacyof this class of compounds.
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