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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

Le Manach, C. and Dam, J. and Woodland, J. G. and Kaur, G. and Khonde, L. P. and Brunschwig, C. and Njoroge, M. and Wicht, K. J. and Horatscheck, A. and Paquet, T. and Boyle, G. A. and Gibhard, L. and Taylor, D. and Lawrence, N. and Yeo, T. and Mok, S. and Eastman, R. T. and Dorjsuren, D. and Talley, D. C. and Guo, H. and Simeonov, A. and Reader, J. and van der Watt, M. and Erlank, E. and Venter, N. and Zawada, J. W. and Aswat, A. and Nardini, L. and Coetzer, T. L. and Lauterbach, S. B. and Bezuidenhout, B. C. and Theron, A. and Mancama, D. and Koekemoer, L. L. and Birkholtz, L. M. and Wittlin, S. and Delves, M. and Ottilie, S. and Winzeler, E. A. and von Geldern, T. W. and Smith, D. and Fidock, D. A. and Street, L. J. and Basarab, G. S. and Duffy, J. and Chibale, K.. (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. Journal of medicinal chemistry, 64 (4). pp. 2291-2309.

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Official URL: https://edoc.unibas.ch/89177/

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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 sp(3)-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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:20 Dec 2022 12:22
Deposited On:20 Dec 2022 12:22

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