Discovery of\nThiophene\nDerivatives as Potent, Orally\nBioavailable, and Blood–Brain Barrier-Permeable Ebola Virus\nEntry Inhibitors

The endemic nature\nof the Ebola virus disease in Africa underscores\nthe need for prophylactic and therapeutic drugs that are affordable\nand easy to administer. Through a phenotypic screening employing viral\npseudotypes and our in-house chemical library, we identified a promising\nhit featuring a thiophene scaffold, exhibiting antiviral activity\nin the micromolar range. Following up on this thiophene hit, a new\nseries of compounds that retain the five-membered heterocyclic scaffold\nwhile modifying several substituents was synthesized. Initial screening\nusing a pseudotype viral system and validation assays employing authentic\nEbola virus demonstrated the potential of this new chemical class\nas viral entry inhibitors. Subsequent investigations elucidated the\nmechanism of action through site-directed mutagenesis. Furthermore,\nwe conducted studies to assess the pharmacokinetic profile of selected\ncompounds to confirm its pharmacological and therapeutic potential.