Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.
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.
Dong
Yuxiang
Y
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
Chollet
Jacques
J
Matile
Hugues
H
Charman
Susan A
SA
Chiu
Francis C K
FC
Charman
William N
WN
Scorneaux
Bernard
B
Urwyler
Heinrich
H
Santo Tomas
Josefina
J
Scheurer
Christian
C
Snyder
Christopher
C
Dorn
Arnulf
A
Wang
Xiaofang
X
Karle
Jean M
JM
Tang
Yuanqing
Y
Wittlin
Sergio
S
Brun
Reto
R
Vennerstrom
Jonathan L
JL
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
D000962:Antimalarials; D010545:Peroxides; D013141:Spiro Compounds; D010126:Ozone; D000218:Adamantane