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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 publication

DOI

10.1002/cmdc.201900329

Type

Journal article

Journal

ChemMedChem

Publication Date

03/07/2019

Volume

14

Pages

1329 - 1335

Addresses

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.

Keywords

Microsomes, Liver, Animals, Humans, Mice, Plasmodium berghei, Plasmodium cynomolgi, Plasmodium falciparum, Acetamides, Antimalarials, Parasitic Sensitivity Tests, Molecular Structure, Structure-Activity Relationship