Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives

Brian Cox; James Duffy; Victor Zdorichenko; Corentin Bellanger; Jessica Hurcum; Benoît Laleu; Kevin I. Booker-Milburn; Luke D. Elliott; Michael Robertson-Ralph; Christopher J. Swain; Stephen J. Bishop; Irene Hallyburton; Mark Anderson

doi:10.1021/acsmedchemlett.0c00486

Escaping from Flatland: Antimalarial Activity of sp³-Rich Bridged Pyrrolidine Derivatives

Brian Cox, James Duffy, Victor Zdorichenko, Corentin Bellanger, Jessica Hurcum, Benoît Laleu, Kevin I. Booker-Milburn, Luke D. Elliott, Michael Robertson-Ralph, Christopher J. Swain, Stephen J. Bishop, Irene Hallyburton, Mark Anderson

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.

Original language	English
Pages (from-to)	2497-2503
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	12
Early online date	10 Nov 2020
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00486
Publication status	Published - 10 Dec 2020

Keywords

3D character
antimalarial
Drug discovery
photochemistry
sp-rich substituted bridged pyrrolidines

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/acsmedchemlett.0c00486

Cite this

Cox, B., Duffy, J., Zdorichenko, V., Bellanger, C., Hurcum, J., Laleu, B., Booker-Milburn, K. I., Elliott, L. D., Robertson-Ralph, M., Swain, C. J., Bishop, S. J., Hallyburton, I., & Anderson, M. (2020). Escaping from Flatland: Antimalarial Activity of sp³-Rich Bridged Pyrrolidine Derivatives. ACS Medicinal Chemistry Letters, 11(12), 2497-2503. https://doi.org/10.1021/acsmedchemlett.0c00486

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title = "Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives",

abstract = "We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality. ",

keywords = "3D character, antimalarial, Drug discovery, photochemistry, sp-rich substituted bridged pyrrolidines",

author = "Brian Cox and James Duffy and Victor Zdorichenko and Corentin Bellanger and Jessica Hurcum and Beno{\^i}t Laleu and Booker-Milburn, {Kevin I.} and Elliott, {Luke D.} and Michael Robertson-Ralph and Swain, {Christopher J.} and Bishop, {Stephen J.} and Irene Hallyburton and Mark Anderson",

note = "Funding Information: We gratefully acknowledge support for Luke Elliott from the Engineering and Physical Sciences Research Council (EP/P013341/1). Publisher Copyright: {\textcopyright} Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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Cox, B, Duffy, J, Zdorichenko, V, Bellanger, C, Hurcum, J, Laleu, B, Booker-Milburn, KI, Elliott, LD, Robertson-Ralph, M, Swain, CJ, Bishop, SJ, Hallyburton, I & Anderson, M 2020, 'Escaping from Flatland: Antimalarial Activity of sp³-Rich Bridged Pyrrolidine Derivatives', ACS Medicinal Chemistry Letters, vol. 11, no. 12, pp. 2497-2503. https://doi.org/10.1021/acsmedchemlett.0c00486

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AU - Hurcum, Jessica

AU - Laleu, Benoît

AU - Booker-Milburn, Kevin I.

AU - Elliott, Luke D.

AU - Robertson-Ralph, Michael

AU - Swain, Christopher J.

AU - Bishop, Stephen J.

AU - Hallyburton, Irene

AU - Anderson, Mark

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