REVERSAL OF CHLOROQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM BY CDR-87209 AND ANALOGS/

The spreading of resistance towards chloroquine has diminished its val ue as a potent and safe drug in malaria endemic areas. Recent reports on the reversal of chloroquine resistance in the malaria parasite Plas modium falciparum in vitro and in vivo by verapamil, desipramine and o ther Ca2+-channel blockers and antideperessants has initiated a strate gy for chemotherapy by treatment with chloroquine in combination with a drug resistance modulator. Described here is a class of modulators o f distinct structure which reverse chloroquine resistance in a differe nt manner. Contrary to verapamil and desipramine, CDRI 87/209, the mos t potent compound of this new class and used as a chemical lead, did n ot restore chloroquine accumulation in the resistant parasites, thereb y indicating that besides the proposed blockade of drug efflux other m echanisms are vulnerable targets for a chemotherapeutic approach towar ds drug resistance. Similar to the former modulators, CDRI 87/209 show ed only weak intrinsic plasmodicidal activity and the increase of drug susceptibility was restricted to resistant plasmodia.