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Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts
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    Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts
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    • Claire Le Manach
      Claire Le Manach
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • Jean Dam
      Jean Dam
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
      More by Jean Dam
    • John G. Woodland
      John G. Woodland
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • Gurminder Kaur
      Gurminder Kaur
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • Lutete P. Khonde
      Lutete P. Khonde
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • Christel Brunschwig
      Christel Brunschwig
      Drug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
    • Mathew Njoroge
      Mathew Njoroge
      Drug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
    • Kathryn J. Wicht
      Kathryn J. Wicht
      Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States
    • André Horatscheck
      André Horatscheck
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • Tanya Paquet
      Tanya Paquet
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
      More by Tanya Paquet
    • Grant A. Boyle
      Grant A. Boyle
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • Liezl Gibhard
      Liezl Gibhard
      Drug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
    • Dale Taylor
      Dale Taylor
      Drug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
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    • Nina Lawrence
      Nina Lawrence
      Drug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
    • Tomas Yeo
      Tomas Yeo
      Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States
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    • Sachel Mok
      Sachel Mok
      Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States
      More by Sachel Mok
    • Richard T. Eastman
      Richard T. Eastman
      Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United States
    • Dorjbal Dorjsuren
      Dorjbal Dorjsuren
      Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United States
    • Daniel C. Talley
      Daniel C. Talley
      Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United States
    • Hui Guo
      Hui Guo
      Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United States
      More by Hui Guo
    • Anton Simeonov
      Anton Simeonov
      Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United States
    • Janette Reader
      Janette Reader
      Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa
    • Mariëtte van der Watt
      Mariëtte van der Watt
      Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa
    • Erica Erlank
      Erica Erlank
      Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
      Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South Africa
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    • Nelius Venter
      Nelius Venter
      Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
      Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South Africa
    • Jacek W. Zawada
      Jacek W. Zawada
      Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
      Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South Africa
    • Ayesha Aswat
      Ayesha Aswat
      Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
      Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South Africa
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    • Luisa Nardini
      Luisa Nardini
      Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
      Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South Africa
    • Theresa L. Coetzer
      Theresa L. Coetzer
      Wits Research Institute for Malaria, School of Pathology, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
    • Sonja B. Lauterbach
      Sonja B. Lauterbach
      Wits Research Institute for Malaria, School of Pathology, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
    • Belinda C. Bezuidenhout
      Belinda C. Bezuidenhout
      Wits Research Institute for Malaria, School of Pathology, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
    • Anjo Theron
      Anjo Theron
      Biosciences, Council for Scientific and Industrial Research, P.O. Box 395, Pretoria 0001, South Africa
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    • Dalu Mancama
      Dalu Mancama
      Biosciences, Council for Scientific and Industrial Research, P.O. Box 395, Pretoria 0001, South Africa
      More by Dalu Mancama
    • Lizette L. Koekemoer
      Lizette L. Koekemoer
      Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa
      Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South Africa
    • Lyn-Marie Birkholtz
      Lyn-Marie Birkholtz
      Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa
    • Sergio Wittlin
      Sergio Wittlin
      Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland
      University of Basel, 4003 Basel, Switzerland
    • Michael Delves
      Michael Delves
      Imperial College London, South Kensington, London SW7 2AZ, U.K.
      London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
    • Sabine Ottilie
      Sabine Ottilie
      Division of Host−Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California 92093-076, United States
    • Elizabeth A. Winzeler
      Elizabeth A. Winzeler
      Division of Host−Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California 92093-076, United States
    • Thomas W. von Geldern
      Thomas W. von Geldern
      Embedded Consulting, P.O. Box 726, Richmond, Illinois 60071, United States
    • Dennis Smith
      Dennis Smith
      4 The Maltings, Walmer CT14 7AR, U.K.
      More by Dennis Smith
    • David A. Fidock
      David A. Fidock
      Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States
      Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States
    • Leslie J. Street
      Leslie J. Street
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • Gregory S. Basarab
      Gregory S. Basarab
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
    • James Duffy
      James Duffy
      Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland
      More by James Duffy
    • Kelly Chibale*
      Kelly Chibale
      Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa
      South African Medical Research Council, Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
      *Email: [email protected]. Phone: +27-21-6502553. Fax: +27-21-6505195.
    Other Access OptionsSupporting Information (4)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 4, 2291–2309
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c00034
    Published February 12, 2021
    Copyright © 2021 American Chemical Society

    Abstract

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    A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure–activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00034.

    • Procedures used for the biological as well as in vitro and in vivo DMPK studies (Supporting Information File 1) (PDF)

    • Additional details of the synthetic protocols and compound characterization (Supporting Information File 2) (PDF)

    • SMFA data (Supporting Information File 3) (XLSX)

    • Excel file with molecular strings (Supporting Information File 4) (CSV)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 4, 2291–2309
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c00034
    Published February 12, 2021
    Copyright © 2021 American Chemical Society

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