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Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

ABSTRACT: 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.

SUBMITTER: Kancharla P 

PROVIDER: S-EPMC7354843 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

Kancharla Papireddy P   Dodean Rozalia A RA   Li Yuexin Y   Pou Sovitj S   Pybus Brandon B   Melendez Victor V   Read Lisa L   Bane Charles E CE   Vesely Brian B   Kreishman-Deitrick Mara M   Black Chad C   Li Qigui Q   Sciotti Richard J RJ   Olmeda Raul R   Luong Thu-Lan TL   Gaona Heather H   Potter Brittney B   Sousa Jason J   Marcsisin Sean S   Caridha Diana D   Xie Lisa L   Vuong Chau C   Zeng Qiang Q   Zhang Jing J   Zhang Ping P   Lin Hsiuling H   Butler Kirk K   Roncal Norma N   Gaynor-Ohnstad Lacy L   Leed Susan E SE   Nolan Christina C   Ceja Frida G FG   Rasmussen Stephanie A SA   Tumwebaze Patrick K PK   Rosenthal Philip J PJ   Mu Jianbing J   Bayles Brett R BR   Cooper Roland A RA   Reynolds Kevin A KA   Smilkstein Martin J MJ   Riscoe Michael K MK   Kelly Jane X JX  

Journal of medicinal chemistry 20200526 11

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-gener  ...[more]

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