Drugs targeting the liver stage offer many advantages over drugs that merely target the blood stage. First, drugs active against the liver stage represent true causally prophylactic agents that can prevent all disease symptoms, including death, associated with malaria. Secondly, it has been established that while wild-caught mosquitoes may harbor thousands of sporozoites, only H10 sporozoites are transferred in a single bite to the human host. Over the next 2-3 weeks the sporozoite reproduces in the liver to produce 10,000-30,000 descendants before the schizont ruptures and parasites flood into the bloodstream where the absolute parasite burden may increase to ten thousand billion (1013) circulating plasmodia. Clearly it is advantageous to strike at the liver stage where parasite numbers are low, to diminish the likelihood of selecting for a drug resistant mutant and before the infection has a chance to weaken the defenses of the human host. Our primary goal in this project is to develop a non-quinoline drug that is active against P. falciparum and P. vivax malaria, targeting the parasite in the liver and blood stages, and including the gametocytes. Studies (by us and others) have shown that the Endochin-like Quinolone (ELQ) chemotype targets all 3 of these life cycle stages. The ultimate objective of our proposed work is the development of an inexpensive ELQ that can be co-formulated with other antimalarials in a synergistic combination to prevent and treat malaria, and can serve to assist in eradication of the disease worldwide. Our study of endochin, a drug discovered by Andersag in the 1940's) showed that the primary cause of its poor performance in mammals is due to its metabolic instability. More recently we have developed ELQ analogs with subnanomolar IC50 values against multidrug resistant and atovaquone resistant parasites, curative efficacy in murine models of malaria at oral doses of 1mg/kg/day, as well as prophylaxis against sporozoite induced infections at 3mg/kg/day (the lowest dose studied). In this application we seek to continue to explore the chemical space around the quinolone chemotype in order to develop this antimalarial class to the fullest of its potential. As described in the narrative of this proposal we have already discovered an ELQ derivative that is curative in malaria infected mice at 0.1mg/kg/day (4 days) via multiple routes of administration.
The Specific Aims of this application are: 1. Lead optimization of ELQ antimalarials, 2. Characterization of the ELQ mechanism(s) of action, and 3. Characterization of ELQ resistance mechanisms and assessment of ELQ resistance frequency in populations of P. falciparum parasites. Development of an ELQ for human use could dramatically change the way in which malaria is managed worldwide. Because ELQs are active against multiple developmental stages of infection they could be used to prevent and treat malaria and also could have a major role in eradicating the disease.
Because ELQs selectively kill malaria parasites in the liver and bloodstream as well as developmental forms involved with transmission of the disease this new class of drugs has the potential to radically change the way in which malaria is managed worldwide. Our proposal seeks to optimize and identify ELQs that rapidly kill malaria parasites at multiple stages of the development cycle that can be used for treatment and prevention of malaria even in the most vulnerable populations, pregnant women, young children, and that can be coformulated with other drugs and used in worldwide eradication campaign.
|Nilsen, Aaron; Miley, Galen P; Forquer, Isaac P et al. (2014) Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers. J Med Chem 57:3818-34|