Imidazoquines as Antimalarial and Antipneumocystis Agents

• Published in: Journal of medicinal chemistry Vol. 52; no. 23; pp. 7800 - 7807
• Main Authors: Vale, Nuno, Prudêncio, Miguel, Marques, Catarina A, Collins, Margaret S, Gut, Jiri, Nogueira, Fátima, Matos, Joana, Rosenthal, Philip J, Cushion, Melanie T, do Rosário, Virgílio E, Mota, Maria M, Moreira, Rui, Gomes, Paula
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2009; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antimalarials - blood; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Cell Line; Chemical Phenomena; Chemistry, Medicinal; Disease Transmission, Infectious; Drug Stability; Female; Humans; Imidazoles - blood; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences & Biomedicine; Liver - parasitology; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Pneumocystis carinii - drug effects; Science & Technology; ANTI-PNEUMOCYSTIS-CARINII; IMIDAZOLIDIN-4-ONE DERIVATIVES; IN-VITRO; TRANSMISSION-BLOCKING ANTIMALARIALS; PLASMODIUM-FALCIPARUM; 8-AMINOQUINOLINES; TRAP MASS-SPECTROMETRY; OPPORTUNISTIC INFECTIONS; PNEUMONIA; PRIMAQUINE; Protozoa; Antimalarial; Apicomplexa; Five membered ring; Peptides; Nitrogen heterocycle; Peptidomimetic compound; Quinoline derivatives; Pneumocystis carinii; In vitro; Fungi; Antiprotozoal agent; Plasmodium falciparum; Antifungal agent; Structure activity relation; Bicyclic compound; Dipeptides; Parasiticide; Aromatic compound; Fungi Imperfecti; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900738c

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.