Imidazoquines as Antimalarial and Antipneumocystis Agents

Abstract

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 towards 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.

Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine‐Resistant Plasmodium falciparum

“…[24] Synchronized ring-stage W2 strain P. falciparum was cultured with test compound at various concentrations (taken from 1000 DMSO stock solutions) in RPMI 1640 medium containing 10 % human serum or 0.5 % Albumax serum substitute. After incubation for 48 h, when control cultures contained new rings, parasites were fixed with 1 % formaldehyde in phosphate-buffered saline (PBS; pH 7.4) for 48 h at room temperature and then labeled with YOYO-1 (1 nm; Molecular Probes) in 0.1 % Triton X-100 in PBS.…”

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

“…Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported [30] and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization (Table 1).…”

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

“…Methods employed were as previously reported by us. 4,5,8 CQ and its acridine analogue 3 were chosen as reference drugs for blood-stage assays, whereas PQ was the reference compound for liver-stage studies.…”

“…8 b Inhibition of liver stage infection by compounds 6 was determined by measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferaseexpressing P. berghei line, PbGFP-Luc con , as previously described. 9 c EC 50 determined through inhibition of Plasmodium falciparum 3D7 LDH activity, these mechanisms.…”