New orally active derivatives of artemisinin with high efficacy against multidrug-resistant malaria in mice.
A new series of ether derivatives of dihydroartemisinin have been prepared and evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by oral route. These new derivatives 7-17 are highly lipophilic (log P in the range of 5.51 to 7.19) as compared with beta-arteether (log P 3.84), and several of them are two- to four-fold more active than beta-arteether. Among the ether derivatives, alpha-isomers are more active than the beta-isomers. The ether derivatives 12alpha and 14alpha, the most active compounds of the series, provided 100% protection to infected mice at 12 mg/kgx4 days. In this model beta-arteether provides 100% and 20% protection at 48 mg/kgx4 days and 24 mg/kgx4 days, respectively.
Singh
Chandan
C
Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow-226001, India. chandancdri@yahoo.com
Chaudhary
Sandeep
S
Puri
Sunil K
SK
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D007536:Isomerism; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010967:Plasmodium yoelii; D013329:Structure-Activity Relationship
D000962:Antimalarials; D037621:Artemisinins; C517064:dihydroartemisinin 2-(biphenyl-2-yloxy)ethyl ether; C517063:dihydroartemisinin 4-biphenylmethyl ether