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

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.