title: Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.
abstract: This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.
authors: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
authors: Yuxiang
authors: Y
authors: Dong
authors: Jacques
authors: J
authors: Chollet
authors: Hugues
authors: H
authors: Matile
authors: Susan A
authors: SA
authors: Charman
authors: Francis C K
authors: FC
authors: Chiu
authors: William N
authors: WN
authors: Charman
authors: Bernard
authors: B
authors: Scorneaux
authors: Heinrich
authors: H
authors: Urwyler
authors: Josefina
authors: J
authors: Santo Tomas
authors: Christian
authors: C
authors: Scheurer
authors: Christopher
authors: C
authors: Snyder
authors: Arnulf
authors: A
authors: Dorn
authors: Xiaofang
authors: X
authors: Wang
authors: Jean M
authors: JM
authors: Karle
authors: Yuanqing
authors: Y
authors: Tang
authors: Sergio
authors: S
authors: Wittlin
authors: Reto
authors: R
authors: Brun
authors: Jonathan L
authors: JL
authors: Vennerstrom
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D004351:Drug Resistance; D006207:Half-Life; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D015162:Micronucleus Tests; D010126:Ozone / Q000737:chemistry*; D010545:Peroxides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D010962:Plasmodium berghei; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D010545:Peroxides; D013141:Spiro Compounds; D010126:Ozone; D000218:Adamantane