Premium
Substituted Aminoacetamides as Novel Leads for Malaria Treatment
Author(s) -
Norcross Neil R.,
Wilson Caroline,
Baragaña Beatriz,
Hallyburton Irene,
OsunaCabello Maria,
Norval Suzanne,
Riley Jennifer,
Fletcher Daniel,
Sinden Robert,
Delves Michael,
Ruecker Andrea,
Duffy Sandra,
Meister Stephan,
AntonovaKoch 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.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900329
Subject(s) - plasmodium falciparum , in vivo , chemistry , drug , drug discovery , solubility , malaria , pharmacokinetics , combinatorial chemistry , biology , biochemistry , pharmacology , immunology , microbiology and biotechnology , organic chemistry
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 μ m . 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.