Discovery of <i>p</i>-Trifluoromethylbenzohydrazide Derivatives as Potent Antiviral Agents against Monkeypox Virus

After the global eradication of smallpox has occurred, Monkeypox virus (MPXV) is nowadays the most significant pathogen affecting humans among orthopoxviruses. The recent growing number of cases worldwide is drawing researchers' attention, prompting for the discovery of new antivirals with optimized synthetic protocols and enhanced efficacy. To date tecovirimat, targeting the membrane-anchored phospholipase p37, is the only drug specifically approved for the treatment of MPXV. In an effort to develop inhibitors with more accessible synthetic protocols and broaden the poorly explored structure-activity relationship (SAR) studies, a new library of tecovirimat analogues has been designed and synthesized. The resulting compounds have been tested in phenotypic assays to evaluate their antiviral inhibitory properties. Spirovirimat (<b>7</b>) was identified as a potent lead compound within this series. Further experiments highlighted that <b>7</b> completely abolished extracellular virus production, and <i>in silico</i> studies suggested that <b>7</b> and tecovirimat target the same protein.