Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses

Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, N-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (1), borne from our previously reported hit-to-lead effort. This secondary round of structure–activity relationship (SAR) involved the design and synthesis of several deconstructed and reconstructed analogs of compound 1, which were then tested against pseudotyped EBOV and MARV. The antiviral activities of the most promising leads were further validated in infectious assays. The optimized analogs exhibited desirable antiviral activity against different ebolaviruses and reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates for in vivo efficacy studies as part of our ongoing drug discovery campaign against EBOV and MARV.