Optimization of endochin-like quinolones for antimalarial activity

Structural analogs of the antimalarial endochin were synthesized and screened for antiplasmodial activity against drug sensitive and multidrug resistant strains of Plasmodium falciparum. Structural features have been identified that are associated with improved potency while other features are associated with equipotency against an atovaquone-resistant clinical isolate. Relative to endochin the most active compound ELQ-121 shows ≈100-fold improvement in IC50 for inhibition of P. falciparum in vitro and it also exhibits enhanced metabolic stability. A polyethylene glycol carbonate ester prodrug of ELQ-121 demonstrated in vivo efficacy against Plasmodium yoelii in mice. This is the first report of an endochin-like quinolone that is efficacious in treating malaria in a mammalian host. [Display omitted] ► Synthesis of endochin analogs with enhanced antiparasitic activity. ► Identification of endochin analogs that are equipotent against multidrug-resistant parasites. ► Identification of endochin analogs that are equipotent against atovaquone resistant parasites. ► Prodrug of endochin analog ELQ-121 cures murine malaria by oral route. Our prior work on tricyclic acridones combined with a desire to minimize the tricyclic system led to an interest in antimalarial quinolones and a reexamination of endochin, an experimental antimalarial from the 1940’s. In the present article, we show that endochin is unstable in the presence of murine, rat, and human microsomes which may explain its relatively poor antimalarial activity in mammalian systems. We also profile the structure–activity relationships of ≈30 endochin-like quinolone (ELQ) analogs and highlight features that are associated with enhanced metabolic stability, potent antiplasmodial activity against multidrug resistant strains of Plasmodium falciparum, and equal activity against an atovaquone-resistant clinical isolate. Our work also features an ELQ construct containing a polyethylene glycol carbonate pro-moiety that is highly efficacious by oral administration in a murine malaria model. These findings provide compelling evidence that development of ELQ therapeutics is feasible.