Ebola virus (EBOV) and Marburg virus (MARV) are non-segmented, negative-sense RNA filoviruses that are associated with hemorrhagic fever and high fatality rates. The 2014-2016 Ebola epidemic in West Africa, which was the largest recorded outbreak; the recent 2018 epidemic in the Democratic Republic of Congo, which is the tenth outbreak since 1976 and the second-biggest Ebola epidemic; and a new outbreak in Guinea, reported in February of 2021, and lack of effective therapies underscore the persistent threat of Ebola epidemics and the need for drug discovery and development efforts to produce both practical and effective treatments. Filoviral glycoprotein (GP), known to facilitate viral infection, has proven to be a drug-targetable site with recent FDA-approved anti-EBOV GP monoclonal antibodies. In our effort to drug development, we have discovered a series of N-substituted furopyrroles that display excellent potency against both MARV and EBOV when tested in an HIV-based pseudovirus assay. Selectivity and potency of these viral fusion inhibitors were improved by structural modifications on the scaffold, including the optimization of the heterocyclic core and the substituents on the amide and benzyl portions of the molecules. The best performing inhibitors resulted in nanomolar EC50 values with selectivity index values higher than 100. These compounds were validated in infectious assays and found to be potent inhibitors of both EBOV and MARV. We were able to develop an adequate structure activity relationship with our derivatives. The lead compounds display excellent potency, in vitro metabolic stability, low cytotoxicity, and broad activity against diverse filoviruses.

N-substituted furopyrroles and thienopyrroles as broad-spectrum EBOV and MARV antifiloviral glycoprotein inhibitors

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ACS Fall 2022

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