Substituted Aminoacetamides as Novel Leads for Malaria Treatment

ChemMedChem. 2019 Jul 17;14(14):1329-1335. doi: 10.1002/cmdc.201900329. Epub 2019 Jul 3.


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.

Keywords: Plasmodium falciparum; aminoacetamides; antimalarial agents; hit optimization; malaria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / pharmacokinetics
  • Acetamides / pharmacology*
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium berghei / drug effects
  • Plasmodium cynomolgi / drug effects
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship


  • Acetamides
  • Antimalarials