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

Scott Eagon, Jared T. Hammill, Martina Sigal, Kevin J. Ahn, Julia E. Tryhorn, Grant Koch, Briana Belanger, Cory A. Chaplan, Lauren Loop, Anna S. Kashtanova, Kenya Yniguez, Horacio Lazaro, Steven P. Wilkinson, Amy L. Rice, Mofolusho O. Falade, Rei Takahashi, Katie Kim, Ashley Cheung, Celine Dibernardo, Joshua J. KimballElizabeth A. Winzeler, Korina Eribez, Nimisha Mittal, Francisco Javier Gamo, Benigno Crespo, Alisje Churchyard, Irene García-Barbazán, Jake Baum, Marc O. Anderson, Benoît Laleu, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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 bc1.

Original languageEnglish
Pages (from-to)11902-11919
Number of pages18
JournalJournal of Medicinal Chemistry
Volume63
Issue number20
DOIs
StatePublished - Oct 22 2020

Bibliographical note

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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