A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline

Glutathione (GSH), which is known to guard Plasmodium falciparum from oxida tive damage, may have an additional protective role by promoting heme catab olism. An elevation of GSH content in parasites leads to increased resistan ce to chloroquine (CQ), while GSH depletion in resistant P. falciparum stra ins is expected to restore the sensitivity to CQ. High intracellular GSH le vels depend inter alia on the efficient reduction of GSSG by glutathione re ductase (GR). On the basis of this hypothesis, we have developed a new stra tegy for overcoming glutathione-dependent 4-aminoquinoline resistance. To d irect both a 4-aminoquinoline and a GR inhibitor to the parasite, double-dr ugs were designed and synthesized. Quinoline-based alcohols (with known ant imalarial activity) were combined with a GR inhibitor via a metabolically l abile ester bond to give double-headed prodrugs. The biochemically most act ive double-drug 7 of this series was then evaluated as a growth inhibitor a gainst six Plasmodium falciparum strains that differed in their degree of r esistance to CQ; the ED50 values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followe d that of CQ in these tests, the double-drug exhibited similar efficiency a gainst all strains, the ED50 being as low as 28 nM. For the ester 7, a dose -dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean surviva l time was determined for the animals treated with 40 mg/kg 7 for 4 days. N o cytotoxicity due to this compound was observed. Work is in progress to ex tend and validate the strategy outlined here.