Reversal of chloroquine resistance in Plasmodium falciparum by CDR 87/209 and analogues.

The spreading of resistance towards chloroquine has diminished its value as a potent and safe drug in malaria endemic areas. Recent reports on the reversal of chloroquine resistance in the malaria parasite Plasmodium falciparum in vitro and in vivo by verapamil, desipramine and other Ca(2+)-channel blockers and antidepressants has initiated a strategy for chemotherapy by treatment with chloroquine in combination with a drug resistance modulator. Described here is a class of modulators of distinct structure which reverse chloroquine resistance in a different manner. Contrary to verapamil and desipramine, CDRI 87/209, the most potent compound of this new class and used as a chemical lead, did not restore chloroquine accumulation in the resistant parasites, thereby indicating that besides the proposed blockade of drug efflux other mechanisms are vulnerable targets for a chemotherapeutic approach towards drug resistance. Similar to the former modulators, CDRI 87/209 showed only weak intrinsic plasmodicidal activity and the increase of drug susceptibility was restricted to resistant plasmodia.