Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials
| Autor: | Yuexin Li, Kirk Butler, Brittney Potter, Qigui Li, Papireddy Kancharla, Roland A. Cooper, Thu Lan Luong, Heather Gaona, Jing Zhang, Richard J. Sciotti, Brian Vesely, Chau Vuong, Qiang Zeng, Sean R. Marcsisin, Michael K. Riscoe, Diana Caridha, Jason C. Sousa, Rolf W. Winter, Norma Roncal, Christina K. Nolan, Lisa Read, Rozalia A. Dodean, Lisa Xie, Lacy Gaynor-Ohnstad, Stephanie J. Huezo, Susan E. Leed, Hsiuling Lin, John C. Tan, Martin J. Smilkstein, Stephanie A Rasmussen, Jane Xu Kelly, Ping Zhang, Chad C. Black, Melissa T. Stephens, Mara Kreishman-Deitrick, Raul Olmeda, Victor Melendez, Sovitj Pou, Charles E. Bane |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Plasmodium
Pharmacology 01 natural sciences Article 03 medical and health sciences chemistry.chemical_compound Antimalarials Mice Structure-Activity Relationship Species Specificity In vivo parasitic diseases Drug Discovery medicine Animals Humans Plasmodium berghei 030304 developmental biology 0303 health sciences biology Drug discovery Chemistry Plasmodium falciparum Hep G2 Cells biology.organism_classification medicine.disease 0104 chemical sciences Malaria Acridone 010404 medicinal & biomolecular chemistry Disease Models Animal Molecular Medicine Plasmodium yoelii Acridones |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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