2. Academic Validation
  3. Discovery of Thiophene Derivatives as Potent, Orally Bioavailable, and Blood-Brain Barrier-Permeable Ebola Virus Entry Inhibitors

Discovery of Thiophene Derivatives as Potent, Orally Bioavailable, and Blood-Brain Barrier-Permeable Ebola Virus Entry Inhibitors

  • J Med Chem. 2024 Sep 26;67(18):16381-16402. doi: 10.1021/acs.jmedchem.4c01267.
Marcos Morales-Tenorio 1,  Fátima Lasala 2,  Alfonso Garcia-Rubia 1,  Elnaz Aledavood 1,  Michelle Heung 3,  Catherine Olal 3,  Beatriz Escudero-Pérez 3,  Covadonga Alonso 4,  Ana Martínez 1 5,  César Muñoz-Fontela 3,  Rafael Delgado 2 6 7,  Carmen Gil 1 5
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 Dpt. Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Madrid 28040, Spain.
  • 5 CIBERNED, Instituto Salud Carlos III, Madrid 28029, Spain.
  • 6 CIBERINFEC, Instituto Salud Carlos III, Madrid 28029, Spain.
  • 7 School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain.
PMID: 39248591 DOI: 10.1021/acs.jmedchem.4c01267
Abstract

The endemic nature of the Ebola virus disease in Africa underscores the need for prophylactic and therapeutic drugs that are affordable and easy to administer. Through a phenotypic screening employing viral pseudotypes and our in-house chemical library, we identified a promising hit featuring a thiophene scaffold, exhibiting Antiviral activity in the micromolar range. Following up on this thiophene hit, a new series of compounds that retain the five-membered heterocyclic scaffold while modifying several substituents was synthesized. Initial screening using a pseudotype viral system and validation assays employing authentic Ebola virus demonstrated the potential of this new chemical class as viral entry inhibitors. Subsequent investigations elucidated the mechanism of action through site-directed mutagenesis. Furthermore, we conducted studies to assess the pharmacokinetic profile of selected compounds to confirm its pharmacological and therapeutic potential.

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