ChemMedChem p. 1329 - 1335 (2019)
Update date:2022-07-29
Topics: Synthesis In vitro Testing In Vivo Testing Chemical Structure Pharmacokinetics Toxicity Efficacy Substituted Aminoacetamides Novel Leads Malaria Treatment
Norcross, Neil R.
Wilson, Caroline
Baraga?a, Beatriz
Hallyburton, Irene
Osuna-Cabello, Maria
Norval, Suzanne
Riley, Jennifer
Fletcher, Daniel
Sinden, Robert
Delves, Michael
Ruecker, Andrea
Duffy, Sandra
Meister, Stephan
Antonova-Koch, Yevgeniya
Crespo, Benigno
de Cózar, Cristina
Sanz, Laura M.
Gamo, Francisco Javier
Avery, Vicky M.
Frearson, Julie A.
Gray, David W.
Fairlamb, Alan H.
Winzeler, Elizabeth A.
Waterson, David
Campbell, Simon F.
Willis, Paul A.
Read, Kevin D.
Gilbert, Ian H.
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.
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Contact:571-81902596
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Doi:10.1016/j.bmcl.2010.09.111
(2010)Doi:10.1039/c0ob00415d
(2010)Doi:10.1002/chem.201001437
(2010)Doi:10.1016/j.tet.2010.09.028
(2010)Doi:10.1016/S0040-4039(00)99253-0
(1989)Doi:10.1021/jo00294a020
(1990)