title: Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres.
abstract: To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.forename: Jacques
authors.initials: J
authors.lastname: Chollet
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Janne
authors.initials: J
authors.lastname: Mannila
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Christian
authors.initials: C
authors.lastname: Scheurer
authors.forename: Jessica
authors.initials: J
authors.lastname: Steuten
authors.forename: Josefina
authors.initials: J
authors.lastname: Santo Tomas
authors.forename: Christopher
authors.initials: C
authors.lastname: Snyder
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000042:Absorption; D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004148:Dioxolanes / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D010545:Peroxides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D045568:Tetraoxanes / Q000737:chemistry*
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D004148:Dioxolanes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D013141:Spiro Compounds; D045568:Tetraoxanes; C489136:arterolane; D000218:Adamantane; C558165:artefenomel; C010962:formal glycol