4-(Aminomethyl) benzamides as novel anti-Ebola agents

Ebola (EBOV) and Marburg (MARV) viruses belong to the Filoviridae family and can cause fatal
hemorrhagic fevers characterized by widespread tissue destruction after an incubation period of
4-14 days. Due to safety concerns, these viruses are designated as biosafety level 4 agents.
Currently, there is no effective vaccine or therapeutic treatment for filoviral infections in humans.
Africa has recently (2014-2016) suffered a lethal EBOV epidemic with 27,000 people infected
and more than11,000 deaths, underscoring the urgency of antiviral drug discovery and
development. This Phase II application proposes to develop potent, small molecule inhibitors,
which block entry of EBOV. We have identified compounds that inhibit entry of infectious
EBOV/MARV with IC50 values in the nanomolar range. In Phase I, we synthesized structurally
diverse analogs of the anti-Ebola CBS1118 hit series based on structure-activity relationships
(SARs), to improve potency and selectivity. Prioritized inhibitors were validated in the infectious
assay. We investigated the mechanism of action (MOA) of selected candidates, and identified
druglike EBOV inhibitors with good in vitro ADME properties. In addition, these inhibitors display
excellent pharmacokinetic parameters in mouse studies, following oral administration. In this
application, we propose to accomplish the following three specific aims: (1) optimize the lead
scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of
the advanced lead compounds with EBOV glycoproteins; and (3) evaluate the in vivo efficacy
and pharmacokinetics/toxicokinetics of the advanced lead compounds.Project Narrative
This project is to discover and develop small molecule entry inhibitors for Ebola viral
infection. The proposed research will help to develop potential anti-Ebola virus
therapeutics.