1. Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity
- Author
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Tamirat Gebru Woldearegai, Andrea Schöler, Yevgeniya Antonova-Koch, Mary Clarke, Daniela Diedrich, Eva Hesping, Thomas Kurz, Jana Held, Marcel K. W. Mackwitz, Finn K. Hansen, Tina S. Skinner-Adams, Laura Limbach, Katherine T. Andrews, and Elizabeth A. Winzeler
- Subjects
Drug ,Plasmodium berghei ,media_common.quotation_subject ,Plasmodium falciparum ,Drug resistance ,01 natural sciences ,Biochemistry ,Article ,Histones ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Peptoids ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,media_common ,Pharmacology ,biology ,010405 organic chemistry ,Organic Chemistry ,Peptoid ,Acetylation ,biology.organism_classification ,0104 chemical sciences ,Histone Deacetylase Inhibitors ,010404 medicinal & biomolecular chemistry ,Histone ,chemistry ,Toxicity ,biology.protein ,Molecular Medicine ,Histone deacetylase ,Dual stage - Abstract
Novel malaria intervention strategies are of great importance due to 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 utilizing a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure-activity as well as structure-toxicity relationships. Most compounds displayed potent activity against asexual blood stage P. falciparum parasites with IC(50) values ranging from 0.0052–0.25 µM and promising selectivity over mammalian cells (SI(Pf3D7/HepG2): 170–1483). In addition, several compounds showed encouraging submicromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound (N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-i-propylbenzamide, 2h) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC(50) (Pf3D7) = 0.0052 µM, IC(50) (PbEEF) = 0.016 µM).
- Published
- 2018