Aminomethyl benzamides as novel anti Ebola agents

Ebola EBOV and Marburg MARV viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of days Because of the safety concerns these viruses are designated as the biosafety level agents Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans Africa has recently suffered a lethal EBOV epidemic with people infected and deaths underscoring the urgency of antiviral drug discovery and development This application defines a plan to develop potent small molecule inhibitors which block entry of EBOV We have identified compounds that inhibit entry of infectious EBOV MARV IC values M These hit compounds exhibit selectivity for EBOV MARV entry The overall objective of this Phase I application is to develop these inhibitors as potential anti EBOV therapeutics This application will focus on the following three specific aims Synthesize structurally diverse analogs of the anti Ebola CBS hit series based on structure activity relationships SARs to improve potency and selectivity Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action MOA of the EBOV inhibitors Select EBOV inhibitors with in vitro ADME properties suitable for i v and oral dosing 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 antiviral therapeutics