New adamantane-based spiro 1,2,4-trioxanes orally effective against rodent and simian malaria.
New 6-arylvinyl- and 6-adamantylvinyl-substituted 1,2,4-trioxanes (13a-g and 14a,b) have been prepared and evaluated for antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular routes. While all the 6-arylvinyl-substituted trioxanes, 13a-f, showed promising activity, none of the 6-adamantylvinyl-substituted trioxanes, 13g and 14a,b, exhibited significant activity. Trioxane, 13f, the most active compound of the series, provided 100% and 80% protection to malaria-infected mice at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively, by oral route. In this model, beta-arteether (3) provided 100% protection at 48 mg/kg x 4 days and only 20% protection at 24 mg/kg x 4 days. Trioxane 13f also showed complete suppression of parasitaemia at 10 mg/kg x 4 days by oral route in rhesus monkeys infected with P. cynomolgi. None of these trioxanes, except 13f, showed significant activity by the intramuscular route.
Singh
Chandan
C
Division of Medicinal and Process Chemistry and Division of Parasitology, Central Drug Research Institute, Lucknow-226001, India. chandancdri@yahoo.com
Kanchan
Rani
R
Sharma
Upasana
U
Puri
Sunil K
SK
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D004351:Drug Resistance; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D016789:Plasmodium cynomolgi / Q000187:drug effects; D010967:Plasmodium yoelii / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C517648:1-(2-fluorenyl)ethenylspiro(1,2,4-trioxane-3,2'-adamantane); D000962:Antimalarials; D006573:Heterocyclic Compounds, 1-Ring; D013141:Spiro Compounds; D000218:Adamantane