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
- Claire Le ManachClaire Le ManachDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Claire Le Manach
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- Jean DamJean DamDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Jean Dam
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- John G. WoodlandJohn G. WoodlandDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by John G. Woodland
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- Gurminder KaurGurminder KaurDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Gurminder Kaur
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- Lutete P. KhondeLutete P. KhondeDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Lutete P. Khonde
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- Christel BrunschwigChristel BrunschwigDrug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South AfricaMore by Christel Brunschwig
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- Mathew NjorogeMathew NjorogeDrug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South AfricaMore by Mathew Njoroge
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- Kathryn J. WichtKathryn J. WichtDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United StatesMore by Kathryn J. Wicht
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- André HoratscheckAndré HoratscheckDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by André Horatscheck
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- Tanya PaquetTanya PaquetDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Tanya Paquet
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- Grant A. BoyleGrant A. BoyleDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Grant A. Boyle
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- Liezl GibhardLiezl GibhardDrug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South AfricaMore by Liezl Gibhard
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- Dale TaylorDale TaylorDrug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South AfricaMore by Dale Taylor
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- Nina LawrenceNina LawrenceDrug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South AfricaMore by Nina Lawrence
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- Tomas YeoTomas YeoDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United StatesMore by Tomas Yeo
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- Sachel MokSachel MokDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United StatesMore by Sachel Mok
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- Richard T. EastmanRichard T. EastmanDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United StatesMore by Richard T. Eastman
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- Dorjbal DorjsurenDorjbal DorjsurenDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United StatesMore by Dorjbal Dorjsuren
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- Daniel C. TalleyDaniel C. TalleyDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United StatesMore by Daniel C. Talley
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- Hui GuoHui GuoDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United StatesMore by Hui Guo
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- Anton SimeonovAnton SimeonovDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, United StatesMore by Anton Simeonov
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- Janette ReaderJanette ReaderDepartment of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South AfricaMore by Janette Reader
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- Mariëtte van der WattMariëtte van der WattDepartment of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South AfricaMore by Mariëtte van der Watt
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- Erica ErlankErica ErlankWits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaCentre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South AfricaMore by Erica Erlank
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- Nelius VenterNelius VenterWits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaCentre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South AfricaMore by Nelius Venter
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- Jacek W. ZawadaJacek W. ZawadaWits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaCentre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South AfricaMore by Jacek W. Zawada
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- Ayesha AswatAyesha AswatWits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaCentre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South AfricaMore by Ayesha Aswat
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- Luisa NardiniLuisa NardiniWits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaCentre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South AfricaMore by Luisa Nardini
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- Theresa L. CoetzerTheresa L. CoetzerWits Research Institute for Malaria, School of Pathology, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaMore by Theresa L. Coetzer
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- Sonja B. LauterbachSonja B. LauterbachWits Research Institute for Malaria, School of Pathology, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaMore by Sonja B. Lauterbach
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- Belinda C. BezuidenhoutBelinda C. BezuidenhoutWits Research Institute for Malaria, School of Pathology, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaMore by Belinda C. Bezuidenhout
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- Anjo TheronAnjo TheronBiosciences, Council for Scientific and Industrial Research, P.O. Box 395, Pretoria 0001, South AfricaMore by Anjo Theron
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- Dalu MancamaDalu MancamaBiosciences, Council for Scientific and Industrial Research, P.O. Box 395, Pretoria 0001, South AfricaMore by Dalu Mancama
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- Lizette L. KoekemoerLizette L. KoekemoerWits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaCentre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2192, South AfricaMore by Lizette L. Koekemoer
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- Lyn-Marie BirkholtzLyn-Marie BirkholtzDepartment of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South AfricaMore by Lyn-Marie Birkholtz
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- Sergio WittlinSergio WittlinSwiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, SwitzerlandUniversity of Basel, 4003 Basel, SwitzerlandMore by Sergio Wittlin
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- Michael DelvesMichael DelvesImperial College London, South Kensington, London SW7 2AZ, U.K.London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.More by Michael Delves
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- Sabine OttilieSabine OttilieDivision of Host−Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California 92093-076, United StatesMore by Sabine Ottilie
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- Elizabeth A. WinzelerElizabeth A. WinzelerDivision of Host−Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California 92093-076, United StatesMore by Elizabeth A. Winzeler
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- Thomas W. von GeldernThomas W. von GeldernEmbedded Consulting, P.O. Box 726, Richmond, Illinois 60071, United StatesMore by Thomas W. von Geldern
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- Dennis Smith
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- David A. FidockDavid A. FidockDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United StatesDivision of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United StatesMore by David A. Fidock
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- Leslie J. StreetLeslie J. StreetDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Leslie J. Street
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- Gregory S. BasarabGregory S. BasarabDrug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaMore by Gregory S. Basarab
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- James DuffyJames DuffyMedicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, SwitzerlandMore by James Duffy
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- Kelly Chibale*Kelly Chibale*Email: [email protected]. Phone: +27-21-6502553. Fax: +27-21-6505195.Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South AfricaSouth 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 AfricaMore by Kelly Chibale
Abstract
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.
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