ABSTRACT
A new series of ester analogues of artemisinin 8a-f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g-j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a-f were found to be 2-4 folds more active than the antimalarial drugs ß-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete protection to the infected mice at 24 mg/kg × 4 days as well as 12 mg/kg × 4 days, respectively. In this model ß-arteether provided 100% and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Artemisinins/administration & dosage , Artemisinins/pharmacology , Drug Resistance, Multiple , Esters/pharmacology , Plasmodium yoelii/drug effects , Administration, Oral , Animals , Antimalarials/administration & dosage , Antimalarials/chemistry , Artemisinins/chemical synthesis , Artemisinins/chemistry , Dose-Response Relationship, Drug , Esters/administration & dosage , Esters/chemistry , Mice , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
By use of artemisinin 1 as the starting material, two new amino- and hydroxy-functionalized 11-azaartemisinins 9 and 11 and their derivatives 12a-g, 13a-g, 14a-g, and 15a-c have been prepared and screened for antimalarial activity by oral route against multidrug-resistant Plasmodium yoelii in Swiss mice. While azaartemisinins 9 and 11 showed only modest activity, several of their derivatives showed high order of antimalarial activity. Biphenyl-based compound 13f, the most active compound of the series, provided 100% and 80% protection to the infected mice at 12 mg/kg × 4 days and 6 mg/kg × 4 days, respectively. Compounds 12f, 13b, 13e, 13g, and 14f showed 100% protection at 12 mg/kg × 4 days, while compounds 12a-c, 14a, 14c-e, 14g, and 15a-c showed similar levels of protection at 24 mg/kg × 4 days. Clinically useful drug ß-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days in this model.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Artemisinins/chemical synthesis , Artemisinins/pharmacology , Plasmodium yoelii/drug effects , Administration, Oral , Animals , Antimalarials/administration & dosage , Artemisinins/administration & dosage , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Drug Resistance, Multiple/drug effects , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mice , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound of the series (compound 25) provided 100% protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, ß-arteether provided 100 and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. Compound 25 displayed a similar in vitro pharmacokinetic profile to that of reference drug ß-arteether. The activity results demonstrated the importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.
