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

Islam K, Carlsson M, Enquist PA, Qian W, Marttila M, Strand M, Ahlm C, Evander M

ACS Omega 7 (8) 6854-6868 [2022-03-01; online 2022-02-16]

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.

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

PubMed 35252679

DOI 10.1021/acsomega.1c06513

Crossref 10.1021/acsomega.1c06513

pmc: PMC8892858

Publications 9.5.0