Substituted Aminoacetamides as Novel Leads for Malaria Treatment
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Author(s)
Norcross, Neil R
Wilson, Caroline
Baragana, 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 Cozar, Cristina
Sanz, Laura M
Javier Gamo, Francisco
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
Year published
2019
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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 ...
View more >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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View more >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.
View less >
Journal Title
ChemMedChem
Volume
14
Issue
14
Copyright Statement
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Subject
Medicinal and biomolecular chemistry
Organic chemistry
Pharmacology and pharmaceutical sciences
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
aminoacetamides