Configurationally Locked Ridaifen-B Analogs as Potent Ebola Virus Entry Inhibitors

In the face of emerging outbreaks, high mortality rates, and limited treatment options, Ebola virus (EBOV) disease poses a global public health threat, underscoring the need for effective therapies. The unique and critical role that EBOV glycoprotein (GP) plays in the viral life cycle makes it an attractive target for antiviral drug discovery. In this study, we report on the design, synthesis, and evaluation of a series of cyclized ridaifen-B-based inhibitors with enhanced antiviral activity and selectivity against EBOV. Several compounds exhibited nanomolar potency inhibiting EBOV-GP-mediated entry and submicromolar potency against Marburg virus entry. Site-directed mutagenesis indicated inhibitor binding at the EBOV GP1/GP2 fusion loop. The compounds displayed favorable in vitro pharmacokinetic parameters, which encouraged testing the in vivo rapid PK for hit compound 41. This study highlights the potential of 1,2-dihydronaphthalene and tetrahydronaphthalene derivatives as valuable leads for the development of potent antifiloviral agents targeting EBOV among other filoviruses.