The structure-activity relationship of the antimalarial ozonide arterolane (OZ277).
The structure and stereochemistry of the cyclohexane substituents of analogues of arterolane (OZ277) had little effect on potency against Plasmodium falciparum in vitro. Weak base functional groups were not required for high antimalarial potency, but they were essential for high antimalarial efficacy in P. berghei-infected mice. Five new ozonides with antimalarial efficacy and ADME profiles superior or equal to that of arterolane were identified.
Dong
Yuxiang
Y
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, USA.
Wittlin
Sergio
S
Sriraghavan
Kamaraj
K
Chollet
Jacques
J
Charman
Susan A
SA
Charman
William N
WN
Scheurer
Christian
C
Urwyler
Heinrich
H
Santo Tomas
Josefina
J
Snyder
Christopher
C
Creek
Darren J
DJ
Morizzi
Julia
J
Koltun
Maria
M
Matile
Hugues
H
Wang
Xiaofang
X
Padmanilayam
Maniyan
M
Tang
Yuanqing
Y
Dorn
Arnulf
A
Brun
Reto
R
Vennerstrom
Jonathan L
JL
D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000962:Antimalarials; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D013141:Spiro Compounds; C489136:arterolane