New chimeric antimalarials with 4-aminoquinoline moiety linked to a tetraoxane skeleton.
The synthesis of the chimeric molecules consisting of two pharmacophores, tetraoxane and 7-chloro-4-aminoquinoline, is reported. The tetraoxanes 2, 4, and 8 show relatively potent in vitro antimalarial activities, with IC90 values for the Plasmodium falciparum strain W2 of 2.26, 12.44, and 10.74 nM, respectively. In addition, two compounds, 2 and 4, cured mice in a modified Thompson test for antimalarial blood stage activity, with a minimum curative dose of 80 mg/kg, a minimum active dose of 20 mg/kg/day, and a maximum tolerated dose of >960 mg/kg.
Opsenica
Igor
I
Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia.
Opsenica
Dejan
D
Lanteri
Charlotte Anne
CA
Anova
Lalaine
L
Milhous
Wilbur K
WK
Smith
Kirsten S
KS
Solaja
Bogdan A
BA
D000634:Aminoquinolines / Q000737:chemistry*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008288:Malaria / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D020714:Maximum Tolerated Dose; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D045568:Tetraoxanes / Q000737:chemistry*
D000634:Aminoquinolines; D000962:Antimalarials; D045568:Tetraoxanes; C047186:7-chloro-4-aminoquinoline