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Structure–Activity and Structure–Toxicity Relationships of Peptoid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Antiplasmodial Activity
Author(s) -
Mackwitz Marcel K. W.,
Hesping Eva,
AntonovaKoch Yevgeniya,
Diedrich Daniela,
Woldearegai Tamirat Gebru,
SkinnerAdams Tina,
Clarke Mary,
Schöler Andrea,
Limbach Laura,
Kurz Thomas,
Winzeler Elizabeth A.,
Held Jana,
Andrews Katherine T.,
Hansen Finn K.
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.201800808
Subject(s) - peptoid , histone deacetylase , plasmodium falciparum , ic50 , chemistry , drug discovery , hdac1 , malaria , pharmacology , structure–activity relationship , histone , stereochemistry , biochemistry , biology , peptide , in vitro , immunology , gene
Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria‐endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid‐based hit compound, we modified all regions of the peptoid scaffold by using a one‐pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure–activity and structure–toxicity relationships. Most compounds displayed potent activity against asexual blood‐stage P. falciparum parasites, with IC 50 values in the range of 0.0052–0.25 μ m and promising selectivity over mammalian cells (SI Pf 3D7/HepG2 : 170–1483). In addition, several compounds showed encouraging sub‐micromolar activity against P. berghei exo‐erythrocytic forms ( Pb EEF). Our study led to the discovery of the hit compound N ‐(2‐(benzylamino)‐2‐oxoethyl)‐ N ‐(4‐(hydroxycarbamoyl)benzyl)‐4‐isopropylbenzamide ( 2 h ) as a potent and parasite‐specific dual‐stage antiplasmodial HDAC inhibitor (IC 50 Pf 3D7=0.0052 μ m , IC 50 Pb EEF=0.016 μ m ).