Antimalarial polyamine analogues.
A series of novel tetraamines of the general formula RNH(CH2)xNH(CH2)yNH(CH2)xNHR was synthesized and examined for activity against growth of Plasmodium falciparum in vitro. Within the series, dibenzyl analogues (R = benzyl) were found to be the most effective growth inhibitors, with IC50 values of about 10(-6) M. Further modifications of the tetraamine provided the optimum chain length for antimalarial activity of y = 7, x = 3. Compound 8 (MDL 27,695) with the structure y = 7, x = 3, R = benzyl, in combination with the ornithine decarboxylase inhibitor alpha-(difluoromethyl)ornithine, resulted in radical cures when tested against experimental Plasmodium berghei infections in mice. The structure-activity relationships of the series are discussed.
Edwards
M L
ML
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Stemerick
D M
DM
Bitonti
A J
AJ
Dumont
J A
JA
McCann
P P
PP
Bey
P
P
Sjoerdsma
A
A
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D011073:Polyamines / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000962:Antimalarials; D011073:Polyamines; C058294:MDL 27695