Synthesis and Structure–Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4‑b]pyridines

Synthesis and Structure–Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4‑b]pyridines

Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo­[3,4-b]­pyridines targeting Plasmodium falciparum, the deadliest s...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 63; no. 20; pp. 11902 - 11919
Main Authors: Eagon, Scott, Hammill, Jared T, Sigal, Martina, Ahn, Kevin J, Tryhorn, Julia E, Koch, Grant, Belanger, Briana, Chaplan, Cory A, Loop, Lauren, Kashtanova, Anna S, Yniguez, Kenya, Lazaro, Horacio, Wilkinson, Steven P, Rice, Amy L, Falade, Mofolusho O, Takahashi, Rei, Kim, Katie, Cheung, Ashley, DiBernardo, Celine, Kimball, Joshua J, Winzeler, Elizabeth A, Eribez, Korina, Mittal, Nimisha, Gamo, Francisco-Javier, Crespo, Benigno, Churchyard, Alisje, García-Barbazán, Irene, Baum, Jake, Anderson, Marc O, Laleu, Benoît, Guy, R. Kiplin
Format: Journal Article
Language:English
Published: United States American Chemical Society 22-10-2020
Subjects:
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Cell Line
Dose-Response Relationship, Drug
Hep G2 Cells
Humans
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum - drug effects
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - pharmacology
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Structure-Activity Relationship
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Summary:Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo­[3,4-b]­pyridines targeting Plasmodium falciparum, the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar in vitro activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines. In addition, our hit compounds show good activity against the liver stage of the parasite but little activity against the gametocyte stage. Parasitological profiles, including rate of killing, docking, and molecular dynamics studies, suggest that our compounds may target the Qo binding site of cytochrome bc 1.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01152