2. Academic Validation
  3. N'-Phenylacetohydrazide Derivatives as Potent Ebola Virus Entry Inhibitors with an Improved Pharmacokinetic Profile

N'-Phenylacetohydrazide Derivatives as Potent Ebola Virus Entry Inhibitors with an Improved Pharmacokinetic Profile

  • J Med Chem. 2023 Apr 27;66(8):5465-5483. doi: 10.1021/acs.jmedchem.2c01785.
Alfonso Garcia-Rubia 1,  Fátima Lasala 2,  Tiziana Ginex 1,  Marcos Morales-Tenorio 1,  Catherine Olal 3,  Michelle Heung 3,  Paola Oquist 4,  Inmaculada Galindo 5,  Miguel Ángel Cuesta-Geijo 5,  José M Casasnovas 6,  Nuria E Campillo 1 7,  Ángeles Canales 4,  Covadonga Alonso 5,  Ana Martínez 1,  César Muñoz-Fontela 3,  Rafael Delgado 2,  Carmen Gil 1
Affiliations

Affiliations

  • 1 Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid 28040, Spain.
  • 2 Instituto de Investigación Hospital 12 de Octubre, Madrid 28041, Spain.
  • 3 Bernhard Nocht Institute for Tropical Medicine, Hamburg 20359, Germany.
  • 4 Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid 28040, Spain.
  • 5 Dpt. Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Madrid 28040, Spain.
  • 6 Centro Nacional de Biotecnología (CNB-CSIC), Madrid 28049, Spain.
  • 7 Instituto de Ciencias Matemáticas (ICMAT-CSIC), Madrid 28049, Spain.
PMID: 37021830 DOI: 10.1021/acs.jmedchem.2c01785
Abstract

Ebola virus (EBOV) is a single-strand RNA virus belonging to the Filoviridae family, which has been associated to most Ebola virus disease outbreaks to date, including the West African and the North Kivu epidemics between 2013 and 2022. This unprecedented health emergency prompted the search for effective medical countermeasures. Following up on the carbazole hit identified in our previous studies, we synthetized a new series of compounds, which demonstrated to prevent EBOV Infection in cells by acting as virus entry inhibitors. The in vitro inhibitory activity was evaluated through the screening against surrogate models based on viral pseudotypes and further confirmed using replicative EBOV. Docking and molecular dynamics simulations joined to saturation transfer difference-nuclear magnetic resonance (STD-NMR) and mutagenesis experiments to elucidate the biological target of the most potent compounds. Finally, in vitro metabolic stability and in vivo pharmacokinetic studies were performed to confirm their therapeutic potential.

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