Synthesis and antimalarial activity of trioxaquine derivatives.
Trioxaquines are dual molecules that contain a trioxane motif linked to an aminoquinoline entity. Among the different compounds of this series, trioxaquine cis-15 (DU1302 c), prepared from alpha-terpinene, a cheap natural product, showed efficient antimalarial activity in vitro on both sensitive and resistant strains of Plasmodium falciparum (IC(50)=5-19 nM). A stereochemical description of this stable, nontoxic, and non-genotoxic antimalarial agent is detailed. Mice infected with P. vinckei were successfully treated with cis-15 in a four-day suppressive test. The doses required to decrease parasitemia by 50 % (ED(50)) were 5 and 18 mg kg(-1) d(-1) after intraperitoneal and oral administration, respectively. Parasitemia clearance was complete without recrudescence at an intraperitoneal dose of 20 mg kg(-1) d(-1).
Dechy-Cabaret
Odile
O
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France.
Benoit-Vical
Françoise
F
Loup
Christophe
C
Robert
Anne
A
Gornitzka
Heinz
H
Bonhoure
Anne
A
Vial
Henri
H
Magnaval
Jean-François
JF
Séguéla
Jean-Paul
JP
Meunier
Bernard
B
D000634:Aminoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000706:statistics & numerical data; D004351:Drug Resistance; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects
D000634:Aminoquinolines; D000962:Antimalarials; D019086:Bridged Bicyclo Compounds, Heterocyclic; C433786:DU 1102; C497428:DU1112; C497429:DU1114; C497427:DU1302c