2. Academic Validation
  3. 1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors

1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors

  • Sci Rep. 2023 Nov 29;13(1):21006. doi: 10.1038/s41598-023-47959-z.
Maurício T Tavares # 1 2,  Arne Krüger # 3,  Sun L Rei Yan 3,  Karoline B Waitman 4,  Vinícius M Gomes 5 6,  Daffiny Sumam de Oliveira 3,  Franciarli Paz 3,  Sebastian Hilscher 7,  Mike Schutkowski 7,  Wolfgang Sippl 7,  Claudia Ruiz 8,  Mônica F Z J Toledo 4,  Neuza M A Hassimotto 9,  João A Machado-Neto 10,  Antti Poso 11 12 13,  Michael D Cameron 8,  Thomas D Bannister 8,  Giuseppe Palmisano 5 6,  Carsten Wrenger 14,  Thales Kronenberger 15 16 17,  Roberto Parise-Filho 18
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 3 Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo, 05508-900, Brazil.
  • 4 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, São Paulo, 05508-000, Brazil.
  • 5 GlycoProteomics Laboratory, Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
  • 6 School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, Australia.
  • 7 Faculty of Biosciences, Martin-Luther-University of Halle-Wittenberg, 06120, Halle/Saale, Germany.
  • 8 Department of Molecular Medicine, The Herbert Wertheim Institute for Biomedical Innovation and Technology, Jupiter, FL, 33458, USA.
  • 9 Food Research Center-(FoRC-CEPID) and Department of Food Science and Nutrition, Faculty of Pharmaceutical Science, University of São Paulo, São Paulo, SP, Brazil.
  • 10 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • 11 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität, Tuebingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
  • 12 Tuebingen Center for Academic Drug Discovery & Development (TüCAD2), 72076, Tübingen, Germany.
  • 13 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
  • 14 Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo, 05508-900, Brazil. [email protected].
  • 15 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität, Tuebingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany. [email protected].
  • 16 Tuebingen Center for Academic Drug Discovery & Development (TüCAD2), 72076, Tübingen, Germany. [email protected].
  • 17 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. [email protected].
  • 18 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, São Paulo, 05508-000, Brazil. [email protected].
  • # Contributed equally.
PMID: 38030668 DOI: 10.1038/s41598-023-47959-z
Abstract

We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a-d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.

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