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. Kimball; Elizabeth 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

doi:10.1021/acs.jmedchem.0c01152

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. Kimball

Elizabeth 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 journal › Article › peer-review

25 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 language	English
Pages (from-to)	11902-11919
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	20
DOIs	https://doi.org/10.1021/acs.jmedchem.0c01152
State	Published - Oct 22 2020

Bibliographical note

Publisher Copyright:
©

Funding

Support for the synthesis of all compounds was provided to S.E., K.J.A., J.E.T., G.K., B.B., C.A.C., L.L., A.S.K., K.Y., and H.L. by the Bill and Linda Frost fund as well as the Research, Scholarly, and Creative Activities (RSCA) program at California Polytechnic State University (no associated grant number). Gamete formation assay support was provided to J.B. and A.C. by the MMV (no. RD-08-2800). J.B. is also supported by an Investigator Award from Wellcome (no. 100993/Z/13/Z). K.E., N.M. and E.A.W. are supported by MMV (no. RD-12-0096).

Funders	Funder number
Bill and Linda Frost
California State Polytechnic University Pomona
Burroughs Wellcome Fund	100993/Z/13/Z
Medicines for Malaria Venture	RD-12-0096

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/acs.jmedchem.0c01152

Cite this

Eagon, S., Hammill, J. T., Sigal, M., Ahn, K. J., Tryhorn, J. E., Koch, G., Belanger, B., Chaplan, C. A., Loop, L., Kashtanova, A. S., Yniguez, K., Lazaro, H., Wilkinson, S. P., Rice, A. L., Falade, M. O., Takahashi, R., Kim, K., Cheung, A., Dibernardo, C., ... Guy, R. K. (2020). Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4- b]pyridines. Journal of Medicinal Chemistry, 63(20), 11902-11919. https://doi.org/10.1021/acs.jmedchem.0c01152

@article{79dfc8aed1e54e4e9e2aa5ab1a55cd49,

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

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.",

author = "Scott Eagon and Hammill, \{Jared T.\} and Martina Sigal and Ahn, \{Kevin J.\} and Tryhorn, \{Julia E.\} and Grant Koch and Briana Belanger and Chaplan, \{Cory A.\} and Lauren Loop and Kashtanova, \{Anna S.\} and Kenya Yniguez and Horacio Lazaro and Wilkinson, \{Steven P.\} and Rice, \{Amy L.\} and Falade, \{Mofolusho O.\} and Rei Takahashi and Katie Kim and Ashley Cheung and Celine Dibernardo and Kimball, \{Joshua J.\} and Winzeler, \{Elizabeth A.\} and Korina Eribez and Nimisha Mittal and Gamo, \{Francisco Javier\} and Benigno Crespo and Alisje Churchyard and Irene Garc{\'i}a-Barbaz{\'a}n and Jake Baum and Anderson, \{Marc O.\} and Beno{\^i}t Laleu and Guy, \{R. Kiplin\}",

note = "Publisher Copyright: {\textcopyright} ",

year = "2020",

month = oct,

day = "22",

doi = "10.1021/acs.jmedchem.0c01152",

language = "English",

volume = "63",

pages = "11902--11919",

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Eagon, S, Hammill, JT, Sigal, M, Ahn, KJ, Tryhorn, JE, Koch, G, Belanger, B, Chaplan, CA, Loop, L, Kashtanova, AS, Yniguez, K, Lazaro, H, Wilkinson, SP, Rice, AL, Falade, MO, Takahashi, R, Kim, K, Cheung, A, Dibernardo, C, Kimball, JJ, Winzeler, EA, Eribez, K, Mittal, N, Gamo, FJ, Crespo, B, Churchyard, A, García-Barbazán, I, Baum, J, Anderson, MO, Laleu, B & Guy, RK 2020, 'Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4- b]pyridines', Journal of Medicinal Chemistry, vol. 63, no. 20, pp. 11902-11919. https://doi.org/10.1021/acs.jmedchem.0c01152

TY - JOUR

T1 - Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4- b]pyridines

AU - Eagon, Scott

AU - Hammill, Jared T.

AU - Sigal, Martina

AU - Ahn, Kevin J.

AU - Tryhorn, Julia E.

AU - Koch, Grant

AU - Belanger, Briana

AU - Chaplan, Cory A.

AU - Loop, Lauren

AU - Kashtanova, Anna S.

AU - Yniguez, Kenya

AU - Lazaro, Horacio

AU - Wilkinson, Steven P.

AU - Rice, Amy L.

AU - Falade, Mofolusho O.

AU - Takahashi, Rei

AU - Kim, Katie

AU - Cheung, Ashley

AU - Dibernardo, Celine

AU - Kimball, Joshua J.

AU - Winzeler, Elizabeth A.

AU - Eribez, Korina

AU - Mittal, Nimisha

AU - Gamo, Francisco Javier

AU - Crespo, Benigno

AU - Churchyard, Alisje

AU - García-Barbazán, Irene

AU - Baum, Jake

AU - Anderson, Marc O.

AU - Laleu, Benoît

AU - Guy, R. Kiplin

PY - 2020/10/22

Y1 - 2020/10/22

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85094221842

UR - https://www.scopus.com/pages/publications/85094221842#tab=citedBy

U2 - 10.1021/acs.jmedchem.0c01152

DO - 10.1021/acs.jmedchem.0c01152

M3 - Article

C2 - 32945666

AN - SCOPUS:85094221842

SN - 0022-2623

VL - 63

SP - 11902

EP - 11919

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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