Fluorinated bioactive small molecules have a remarkable role in modern medicinal chemistry, as the incorporation of fluorine into drug candidates enhances their bioavailablility, metabolic stability, binding affinity to target proteins, and provides a variety of beneficial pharmacological properties . One such compound is 5-fluorouracil (5-FU), a fluoropyrimidine antimetabolite commonly used to treat colorectal cancer. A lipophilic-masked analog of 5-FU, carmofur, was developed as an antineoplastic agent which covalently inhibits acid ceramidase, leading to ceramidase-induced apoptosis . Through recent drug repurposing efforts, carmofur has been identified as a potent covalent inhibitor of SARS-CoV-2 main protease (M pro ) activity, suggesting carmofur might be a novel antiviral lead for SARS-CoV-2 (Fig. ).