Antimalarial activity of novel pyrrolizidinyl derivatives of 4-aminoquinolines

Analogues of chloroquine (CQ) and uinacrine, whose 4-diethylamino-1-methylbutyl chain is replaced by a quinolizidinyl or a quinolizidinylalkyl moiety show remarkable antimalarial activity against CQ-S and CQ-R strains of P. falciparum in vitro and against P.berghei and P.yoelii murine infections in vivo (Sparatore A et al 2005). Therefore, the presence of a bulky, strongly basic and lipophilic bicyclic moiety (as the quinolizidine ring), which is not supposed to be easily metabolised, appears an interesting structural feature to overcome resistance. To obtain similar compounds cheaper and easier to synthesise, we prepared and studied two novel analogues of CQ (MG2 and MG3), in which the 4-amino group of the quinoline is linked to a pirrolizidinyl-alkyl moiety. The bulky, basic and lipophilic head is still present, but the bicyclic ring is linked in a way to prevent the chirality (that was present in the quinolizidinyl analogues). Compounds MG2 and MG3 were very active against CQ–S and CQ-R strains of P. falciparum. No toxicity against mammalian cells was observed. They both inhibit beta-haematin formation in the BHIA assay suggesting interference with the heme detoxification process of parasites as mechanism of action, similarly to CQ. In vivo MG2 and MG3 inhibit parasitemia by 100% when given at 10 mg/kg per os against P. berghei in a murine standard 4-days test. The mean survival was 25.7 and 29.3 days when MG3 (10 mg/kg) was given per os (22.3 days for CQ, 0/3 mice cured) or s.c. (15.7 for CQ) respectively and 2/3 mice were parasite free on day 30