Synthesis of isoquinuclidine analogs of chloroquine: Antimalarial and antileishmanial activity

The synthesis of new chloroquine analogs is reported. Some analogs showed good antimalarial activity against both chloroquine-susceptible D6 and the -resistant W2 strains of Plasmodium falciparum. All analogs also demonstrated significant antileishmanial activity. The isoquinuclidine (2-azabicyclo[2.2.2]octane) ring system may be viewed as a semi-rigid boat form of the piperidine ring and, when properly substituted, a scaffold for rigid analogs of biologically active ethanolamines and propanolamines. It is present in natural products (such as ibogaine and dioscorine) that display interesting pharmacological properties. In this study, we have expanded our continuing efforts to incorporate this ring system in numerous pharmacophores, by designing and synthesizing semirigid analogs of the antimalarial drug chloroquine. The analogs were tested in vitro against Plasmodium falciparum strains and Leishmania donovani promastigote cultures. Compounds 6 and 13 displayed potent antimalarial activity against both chloroquine-susceptible D6 and the -resistant W2 strains of P. falciparum. All analogs also demonstrated significant antileishmanial activity with compounds 6 and 13 again being the most potent. The fact that these compounds are active against both chloroquine-resistant and chloroquine-sensitive strains as well as leishmanial cells makes them promising candidates for drug development.