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Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.

ABSTRACT: Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

SUBMITTER: Dodean RA

PROVIDER: S-EPMC6822569 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.

Dodean Rozalia A RA Kancharla Papireddy P Li Yuexin Y 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 Huezo Stephanie J SJ Rasmussen Stephanie A SA Stephens Melissa T MT Tan John C JC Cooper Roland A RA Smilkstein Martin J MJ Pou Sovitj S Winter Rolf W RW Riscoe Michael K MK Kelly Jane X JX

Journal of medicinal chemistry 20190321 7

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmod ...[more]

PMID: 30852885

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Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.

Publications

Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.

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