Imidazoquines as antimalarial and antipneumocystis agents.
Peptidomimetic imidazolidin-4-one derivatives of primaquine (imidazoquines) recently displayed in vitro activity against blood schizonts of a chloroquine-resistant strain of Plasmodium falciparum. Preliminary studies with a subset of such imidazoquines showed them to both block transmission of P. berghei malaria from mouse to mosquito and be highly stable toward hydrolysis at physiological conditions. This prompted us to have deeper insight into the activity of imidazoquines against both Plasmodia and Pneumocystis carinii, on which primaquine is also active. Full assessment of the in vivo transmission-blocking activity of imidazoquines, in vitro tissue-schizontocidal activity on P. berghei-infected hepatocytes, and in vitro anti-P. carinii activity is now reported. All compounds were active in these biological assays, with generally lower activity than the parent drug. However, imidazoquines' stability against both oxidative deamination and proteolytic degradation suggest that they will probably have higher oral bioavailability and lower hematotoxicity than primaquine, which might translate into higher therapeutic indexes.
Departamento de Quimica, Faculdade de Ciencias, Centro de Investigacão em Química da Universidade do Porto, Universidade do Porto, Rua do Campo Alegre 687, P-4169-007 Porto, Portugal.
Nuno
N
Vale
Miguel
M
Prudêncio
Catarina A
CA
Marques
Margaret S
MS
Collins
Jiri
J
Gut
Fátima
F
Nogueira
Joana
J
Matos
Philip J
PJ
Rosenthal
Melanie T
MT
Cushion
Virgílio E
VE
do Rosário
Maria M
MM
Mota
Rui
R
Moreira
Paula
P
Gomes
D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D055598:Chemical Phenomena; D018562:Disease Transmission, Infectious; D004355:Drug Stability; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000469:parasitology; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D045363:Pneumocystis carinii / Q000187:drug effects*
D000962:Antimalarials; D007093:Imidazoles