2. Academic Validation
  3. Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity

Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity

  • Eur J Med Chem. 2024 Nov 5:277:116782. doi: 10.1016/j.ejmech.2024.116782.
Daniel Stopper 1,  Lais Pessanha de Carvalho 2,  Mariana Laureano de Souza 3,  Cindy-Esther Kponomaizoun 1,  Elizabeth A Winzeler 3,  Jana Held 4,  Finn K Hansen 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121, Bonn, Germany.
  • 2 Institute of Tropical Medicine, University of Tübingen, 72074, Tübingen, Germany.
  • 3 Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, United States.
  • 4 Institute of Tropical Medicine, University of Tübingen, 72074, Tübingen, Germany; German Center for Infection Research, Partner Site Tübingen, Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.
  • 5 Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121, Bonn, Germany. Electronic address: finn.hansen@uni-bonn.de.
PMID: 39208744 DOI: 10.1016/j.ejmech.2024.116782
Abstract

Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria Parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC50Pf3D7 = 30 nM; IC50PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC50PbEEF = 0.25 μM), excellent microsomal stability (t1/2 > 60 min), and low cytotoxicity to HEK293 cells (IC50 = 136 μM).

Keywords

HDAC inhibitors; Histone deacetylase; Malaria; Multicomponent reaction; Peptoid.

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