Imidazolidin-4-one peptidomimetic derivatives of primaquine: synthesis and antimalarial activity.
The synthesis of imidazolidin-4-one derivatives of primaquine containing the five-membered ring at the C-terminus of a dipeptide backbone coupled to the parent drug is described. These peptidomimetic derivatives were active against a chloroquine-resistant Plasmodium falciparum strain and inhibited the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The novel imidazolidin-4-ones are extremely stable, both in human plasma and in pH 7.4 buffer, as a result of N(1)-acylation. Thus, 'internal' imidazolidin-4-ones derived from dipeptidyl 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships.
CIQUP, Departamento de Química, Faculdade de Ciências, Universidade do Porto, P-4169-007 Porto, Portugal.
Nuno
N
Vale
Joana
J
Matos
Jiri
J
Gut
Fátima
F
Nogueira
Virgílio
V
do Rosário
Philip J
PJ
Rosenthal
Rui
R
Moreira
Paula
P
Gomes
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D002855:Chromatography, Thin Layer / Q000379:methods; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000097:blood / Q000188:drug therapy; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry*; D010962:Plasmodium berghei / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism; D011319:Primaquine / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D007093:Imidazoles; D010455:Peptides; D011319:Primaquine