Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Neil Norcross, Caroline Wilson, Beatriz Baragana, Irene Hallyburton, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Daniel Fletcher, Robert Sinden, Michael J. Delves, Andrea Ruecker, Sandra Duffy, Stephan Meister, Yevgeniya Antonova-Koch, Benigno Crespo, Cristina de Cózar, Laura Sanz, Francisco-Javier Gamo, Vicky M. Avery, Julie A. FrearsonDavid Gray, Alan Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul Willis, Kevin Read, Ian Gilbert

Research output: Contribution to journalArticle

2 Citations (Scopus)
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Abstract

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.

Original languageEnglish
Pages (from-to)1329-1335
Number of pages7
JournalChemMedChem
Volume14
Issue number14
Early online date12 Jun 2019
DOIs
Publication statusPublished - 17 Jul 2019

Keywords

  • Plasmodium falciparum
  • aminoacetamides
  • antimalarial agents
  • hit optimization
  • malaria

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    Norcross, N., Wilson, C., Baragana, B., Hallyburton, I., Osuna-Cabello, M., Norval, S., Riley, J., Fletcher, D., Sinden, R., Delves, M. J., Ruecker, A., Duffy, S., Meister, S., Antonova-Koch, Y., Crespo, B., de Cózar, C., Sanz, L., Gamo, F-J., Avery, V. M., ... Gilbert, I. (2019). Substituted Aminoacetamides as Novel Leads for Malaria Treatment. ChemMedChem, 14(14), 1329-1335. https://doi.org/10.1002/cmdc.201900329