Novel Synergistic Antimalarials with Resistance Reversal Function

尽管为根除疟疾作出了广泛努力，但疟疾的全球影响仍然令人震惊。这个

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. The devastating situation is largely attributed to and aggravated by the emergence and spread of multidrug- resistant Plasmodium falciparum, the cause of the deadliest form of malaria. Preventing and delaying emergence of drug-resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug resistant malaria. The novel chemotype described in this proposal represents a revolutionary approach. It specifically aims to exploit the strengths of other compounds with ideal traits by making possible a new combination therapy strategy. Our innovative design addresses an immutable parasite target and merges intrinsic potency with resistance-counteracting functions in a single molecule. It represents a novel strategy to expand, enhance, and sustain effective antimalarial drug combinations. Our proposed work in this application seeks to develop novel, potent, safe, inexpensive, and sustainable antimalarial that can be co- formulated with other antimalarials in a synergistic combination to treat malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to maximize the antimalarial potential of the dual- function acridone chemotype through structural optimization for potency, synergy, pharmacology and metabolic stability; to accomplish preclinical assessment of lead candidates that are developed through this program of research; to evaluate for safety, to investigate the mode of action(s) for these synergistic antimalarial acridones, and to explore the propensity for drug resistance to selected acridone candidates.