Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite <i>Plasmodium falciparum</i> and Optimization Efforts
Claire Le Manach, Jean Dam, John G. Woodland, Gurminder Kaur, Lutete Peguy Khonde, Christel Brunschwig, Mathew Njoroge, Kathryn J. Wicht, André Horatscheck, Tanya Paquet, Grant A. Boyle, Liezl Gibhard, Dale Taylor, Nina Lawrence, Tomas Yeo, Sachel Mok, Richard T. Eastman, Dorjbal Dorjsuren, Daniel C. Talley, Hui Guo, Anton Simeonov, Janette Reader, Mariëtte van der Watt, Erica Erlank, Nelius Venter, Jacek W. Zawada, Ayesha S. Aswat, Luisa Nardini, Thérèsa L. Coetzer, Sonja B. Lauterbach, Belinda Bezuidenhout, Anjo Theron, Dalu Mancama, Lizette L. Koekemoer, Lyn‐Marié Birkholtz, Sergio Wittlin, Michael J. Delves, Sabine Ottilie, Elizabeth A. Winzeler, Thomas W von Geldern, Dennis H. Smith, David A. Fidock, Leslie J. Street, Gregory S. Basarab, James Duffy, 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 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.