Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite and Optimization Efforts.

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Journal of medicinal chemistry, Volume: 64, Issue: 4
February 25, 2021
Claire Le Manach C, Jean Dam J, John G Woodland JG, Gurminder Kaur G, Lutete P Khonde LP, Christel Brunschwig C, Mathew Njoroge M, Kathryn J Wicht KJ, André Horatscheck A, Tanya Paquet T, Grant A Boyle GA, Liezl Gibhard L, Dale Taylor D, Nina Lawrence N, Tomas Yeo T, Sachel Mok S, Richard T Eastman RT, Dorjbal Dorjsuren D, Daniel C Talley DC, Hui Guo H, Anton Simeonov A, Janette Reader J, Mariëtte van der Watt M, Erica Erlank E, Nelius Venter N, Jacek W Zawada JW, Ayesha Aswat A, Luisa Nardini L, Theresa L Coetzer TL, Sonja B Lauterbach SB, Belinda C Bezuidenhout BC, Anjo Theron A, Dalu Mancama D, Lizette L Koekemoer LL, Lyn-Marie Birkholtz LM, Sergio Wittlin S, Michael Delves M, Sabine Ottilie S, Elizabeth A Winzeler EA, Thomas W von Geldern TW, Dennis Smith D, David A Fidock DA, Leslie J Street LJ, Gregory S Basarab GS, James Duffy J, Kelly Chibale K

A novel diazaspiro[3.4]octane series was identified from a whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp-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 cyclic amine resistance locus in the mode of resistance.

Courtesy of the U.S. National Library of Medicine