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The Rift Valley fever virus (RVFV) is an emerging high-priority pathogen endemic in Africa with pandemic potential. There is no specific treatment or approved antiviral drugs for the RVFV. We previously developed a cell-based high-throughput assay to screen small molecules targeting the RVFV and identified a potential effective antiviral compound (1- N -(2-(biphenyl-4-yloxy)ethyl)propane-1,3-diamine) as a lead compound. Here, we investigated how structural modifications of the lead compound affected the biological properties and the antiviral effect against the RVFV. We found that the length of the 2-(3-aminopropylamino)ethyl chain of the compound was important for the compound to retain its antiviral activity. The antiviral activity was similar when the 2-(3-aminopropylamino)ethyl chain was replaced with a butyl piperazine chain. However, we could improve the cytotoxicity profile of the lead compound by changing the phenyl piperazine linker from the para -position (compound 9a ) to the meta -position (compound 13a ). Results from time-of-addition studies suggested that compound 13a might be active during virus post-entry and/or the replication phase of the virus life cycle and seemed to affect the K + channel. The modifications improved the properties of our lead compound, and our data suggest that 13a is a promising candidate to evaluate further as a therapeutic agent for RVFV infection.

Structural Modifications and Biological Evaluations of Rift Valley Fever Virus Inhibitors Identified from Chemical Library Screening