title: Blood schizontocidal activity of selected 1,2,4-trioxanes (Fenozans) against the multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) in vivo.
abstract: Blood schizontocidal activity of 10 selected cis-fused cyclopenteno-1,2,4-trioxanes (namely Fenozan compound nos 6, 7, 11, 27, 32, 39, 44, 45, 48 and 51) have been re-investigated to establish their curative doses against the multidrug-resistant Plasmodium yoelii nigeriensis strain, which is lethal in Swiss mice. Freshly prepared formulations of these compounds prepared either in neutral groundnut (peanut) oil or in dimethyl sulfoxide (DMSO)-Tween-water, were compared for their antimalarial activity. Only 2 compounds, namely Fenozan derivatives 11 and 45, formulated in neutral groundnut oil for oral administration, showed highest activity with 100% cure rate in MDR P. yoelii nigeriensis-infected mice, while the DMSO-Tween-water formulations were inactive. Fenozan-48 produced 72.2% cure, when administered orally in groundnut oil (formulation) while its DMSO-Tween formulation was inactive. In the case of Fenozan 7, the oil and DMSO-Tween formulations produced 92.3 and 76.0% cures respectively. Fenozan derivatives nos 6, 27, 32, 39, 44 and 51 were not protective either in groundnut oil or DMSO-Tween oral formulations. The present study has applied more rigorous criteria for selection of active compounds, and has identified the 3,3-spirocyclopentane derivative Fenozan 11, and the 3,3-spirohydropyran derivative Fenozan 45, as potential blood schizontocides which can completely eliminate multidrug-resistant malaria infection in mice. Both these compounds are candidates for pre-clinical development. The present study advocates the preferred use of an oil vehicle for oral evaluation of potential antimalarial trioxanes/fenozans instead of the DMSO formulation, which gives inferior curative efficacy.
authors.affiliation: Division of Parasitology, Central Drug Research Institute, Lucknow, India. renu1113@rediffmail.com
authors.forename: R
authors.initials: R
authors.lastname: Tripathi
authors.forename: C W
authors.initials: CW
authors.lastname: Jefford
authors.forename: G P
authors.initials: GP
authors.lastname: Dutta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D001681:Biological Assay; D018432:Drug Resistance, Multiple; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D000074241:Peanut Oil; D010666:Phenylpropionates / Q000494:pharmacology* / Q000627:therapeutic use; D010938:Plant Oils / Q000494:pharmacology; D010967:Plasmodium yoelii / Q000187:drug effects*; D011897:Random Allocation; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D000074241:Peanut Oil; D010666:Phenylpropionates; D010938:Plant Oils; C047854:fenozan