Substituted Aminoacetamides as Novel Leads for Malaria Treatment.

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

ChemMedChem, Volume: 14, Issue: 14
July 17, 2019
Neil R Norcross NR, Caroline Wilson C, Beatriz Baragaña B, Irene Hallyburton I, Maria Osuna-Cabello M, Suzanne Norval S, Jennifer Riley J, Daniel Fletcher D, Robert Sinden R, Michael Delves M, Andrea Ruecker A, Sandra Duffy S, Stephan Meister S, Yevgeniya Antonova-Koch Y, Benigno Crespo B, Cristina de Cózar C, Laura M Sanz LM, Francisco Javier Gamo FJ, Vicky M Avery VM, Julie A Frearson JA, David W Gray DW, Alan H Fairlamb AH, Elizabeth A Winzeler EA, David Waterson D, Simon F Campbell SF, Paul A Willis PA, Kevin D Read KD, Ian H Gilbert IH

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.

Courtesy of the U.S. National Library of Medicine