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DOI 10.1021/acs.jmedchem.1c00034

Медицинская библиотека · Journal of medicinal chemistry · 2021

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.

Le Manach Claire, Dam Jean, Woodland John G, Kaur Gurminder, Khonde Lutete P, Brunschwig Christel, Njoroge Mathew, Wicht Kathryn J, Horatscheck André, Paquet Tanya, Boyle Grant A, Gibhard Liezl, Taylor Dale, Lawrence Nina, Yeo Tomas, Mok Sachel, Eastman Richard T, Dorjsuren Dorjbal, Talley Daniel C, Guo Hui, Simeonov Anton, Reader Janette, van der Watt Mariëtte, Erlank Erica, Venter Nelius, Zawada Jacek W, Aswat Ayesha, Nardini Luisa, Coetzer Theresa L, Lauterbach Sonja B, Bezuidenhout Belinda C, Theron Anjo, Mancama Dalu, Koekemoer Lizette L, Birkholtz Lyn-Marie, Wittlin Sergio, Delves Michael, Ottilie Sabine, Winzeler Elizabeth A, von Geldern Thomas W, Smith Dennis, Fidock David A, Street Leslie J, Basarab Gregory S, Duffy James, Chibale Kelly

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Аннотация

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.

Для цитирования: Le Manach Claire, Dam Jean, Woodland John G, Kaur Gurminder, Khonde Lutete P, Brunschwig Christel, Njoroge Mathew, Wicht Kathryn J, Horatscheck André, Paquet Tanya, Boyle Grant A, Gibhard Liezl, Taylor Dale, Lawrence Nina, Yeo Tomas, Mok Sachel, Eastman Richard T, Dorjsuren Dorjbal, Talley Daniel C, Guo Hui, Simeonov Anton, Reader Janette, van der Watt Mariëtte, Erlank Erica, Venter Nelius, Zawada Jacek W, Aswat Ayesha, Nardini Luisa, Coetzer Theresa L, Lauterbach Sonja B, Bezuidenhout Belinda C, Theron Anjo, Mancama Dalu, Koekemoer Lizette L, Birkholtz Lyn-Marie, Wittlin Sergio, Delves Michael, Ottilie Sabine, Winzeler Elizabeth A, von Geldern Thomas W, Smith Dennis, Fidock David A, Street Leslie J, Basarab Gregory S, Duffy James, Chibale Kelly. 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.. Journal of medicinal chemistry. 2021. DOI: 10.1021/acs.jmedchem.1c00034.

Предметные рубрики MeSH

AnimalsAnophelesAntimalarialsFemaleGerm CellsHigh-Throughput Screening AssaysHumansMaleMiceMicrosomes, LiverMolecular StructureParasitic Sensitivity TestsPlasmodium falciparumRatsSpiro CompoundsStructure-Activity Relationship
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