2. Academic Validation
  3. One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites

One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites

  • Eur J Med Chem. 2018 Oct 5:158:801-813. doi: 10.1016/j.ejmech.2018.09.018.
Daniela Diedrich 1,  Katharina Stenzel 2,  Eva Hesping 3,  Yevgeniya Antonova-Koch 4,  Tamirat Gebru 5,  Sandra Duffy 3,  Gillian Fisher 3,  Andrea Schöler 6,  Stephan Meister 4,  Thomas Kurz 1,  Vicky M Avery 3,  Elizabeth A Winzeler 4,  Jana Held 5,  Katherine T Andrews 7,  Finn K Hansen 8
Affiliations

Affiliations

  • 1 Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
  • 2 Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany; Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan Campus, QLD, 4111, Australia.
  • 3 Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan Campus, QLD, 4111, Australia.
  • 4 Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States.
  • 5 Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Wilhelmstraße 27, 72074, Tübingen, Germany.
  • 6 Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Medical Faculty, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
  • 7 Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan Campus, QLD, 4111, Australia. Electronic address: k.andrews@griffith.edu.au.
  • 8 Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany; Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Medical Faculty, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany. Electronic address: finn.hansen@uni-leipzig.de.
PMID: 30245402 DOI: 10.1016/j.ejmech.2018.09.018
Abstract

Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or Parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug-sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P. berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC50: 4 nM; Pf Dd2 IC50: 1 nM) and P. berghei exo-erythrocytic forms (Pb EEF IC50: 25 nM) with promising parasite-specific activity (SIPf3D7/HepG2: 2496, SIPfDd2/HepG2: 9990, and SIPbEEF/HepG2: 400).

Keywords

HDAC inhibitor; Histone deacetylase; Malaria; Peptoid; Plasmodium falciparum.

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