In vivo evaluation of quinolizidinyl-and quinolizidinylalkyl-derivatives of 4-aminoquinoline using the murine malaria model Plasmodium berghei/anopheles stephensi

We have previously reported that 4-aminoquinoline derivatives, characterized by the presence of a quinolizidine ring (octahydro-2H-quinolizine), can overcome chloroquine (CQ) resistance, exhibiting strong in vitro antimalarial activity against both CQ-sensitive (CQ-S) and CQ-resistant (CQ-R) strains of P. falciparum (Sparatore A. et al. 2005). Here, we show the in vivo efficacy of three of these compounds AM1, AP4a and AP4b, tested with the murine malaria model Plasmodium berghei (CQ-S)/Balb/c mice and Anopheles stephensi mosquitoes. A complete suppression of parasitaemia was observed with AM1, AP4a and AP4b when administered ip to mice at 10-25 mg/kg. Oral administration of AM1, AP4a and AP4b at different dosages revealed IC50 values of 5.1, 4.7 and 3.3 mg/kg, respectively, that is very similar to that of CQ (3.8 mg/kg). None of the compounds exhibited prophylactic activity and no interference with the development of the parasites in the vector could be evidenced when Anopheles females were fed on AP4a and AP4b treated gametocytic mice. This in vivo evaluation showed that the new 4-aminoquinoline compounds are as effective as CQ on asexual blood stages and thus, on the basis of their chemical and parasitological characteristics, as well as their low toxicity, they can be considered promising leads to develop effective antimalarial agents. The financial support from the University of Camerino, WHO Roll Back Malaria Initiative and the EU 018834 ANTIMAL is acknowledged.