Antimalarial activity of N-alkyl amine, carboxamide, sulfonamide, and urea derivatives of a dispiro-1,2,4-trioxolane piperidine.
With an aim to identify a dispiro-1,2,4-trioxolane with high oral activity and good physicochemical properties, 27 derivatives of an achiral piperidine trioxolane were synthesized; most were potent antimalarial peroxides with IC(50)s ranging from 0.20 to 7.0 ng/mL. The oral efficacies of two of these were superior to artesunate and comparable to artemether. The attractive chemical simplicity of these compounds is balanced only by an apparent metabolic susceptibility.
Padmanilayam
Maniyan
M
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, USA.
Scorneaux
Bernard
B
Dong
Yuxiang
Y
Chollet
Jacques
J
Matile
Hugues
H
Charman
Susan A
SA
Creek
Darren J
DJ
Charman
William N
WN
Tomas
Josefina Santo
JS
Scheurer
Christian
C
Wittlin
Sergio
S
Brun
Reto
R
Vennerstrom
Jonathan L
JL
D000588:Amines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008862:Microsomes, Liver / Q000502:physiology; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014508:Urea / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000588:Amines; D000962:Antimalarials; D010880:Piperidines; D013449:Sulfonamides; D014508:Urea