Journal of Medicinal Chemistry p. 3475 - 3502 (2019)
Update date:2022-08-15
Topics:
Dodean, Rozalia A.
Kancharla, Papireddy
Li, Yuexin
Melendez, Victor
Read, Lisa
Bane, Charles E.
Vesely, Brian
Kreishman-Deitrick, Mara
Black, Chad
Li, Qigui
Sciotti, Richard J.
Olmeda, Raul
Luong, Thu-Lan
Gaona, Heather
Potter, Brittney
Sousa, Jason
Marcsisin, Sean
Caridha, Diana
Xie, Lisa
Vuong, Chau
Zeng, Qiang
Zhang, Jing
Zhang, Ping
Lin, Hsiuling
Butler, Kirk
Roncal, Norma
Gaynor-Ohnstad, Lacy
Leed, Susan E.
Nolan, Christina
Huezo, Stephanie J.
Rasmussen, Stephanie A.
Stephens, Melissa T.
Tan, John C.
Cooper, Roland A.
Smilkstein, Martin J.
Pou, Sovitj
Winter, Rolf W.
Riscoe, Michael K.
Kelly, Jane X.
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.
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