Lead Optimization of Second-Generation Acridones As Broad-Spectrum Antimalarials
This project was supported by NIH/NIAID (award 1R01AI093784) and DOD/PRMRP (award PR160693/W81XWH-17-2-0041).
Journal of Medicinal Chemistry
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.
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Kancharla, P., Dodean, R. A., Li, Y., Pou, S., Pybus, B., Melendez, V., Read, L., Bane, C. E., Vesely, B., Kreishman-Deitrick, M., Black, C., Li, Q., Sciotti, R. J., Olmeda, R., Luong, T.-L., Gaona, H., Potter, B., Sousa, J., Marcsisin, S., … Kelly, J. X. (2020). Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials. Journal of Medicinal Chemistry, 63(11), 6179–6202. https://doi.org/10.1021/ACS.JMEDCHEM.0C00539