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TMPRSS2 is a key protease for SARS\u2010CoV\u20102 entry into host cells, making it a promising drug target since blocking viral entry, viral replication is stopped. We have designed five families of guanidinium derivatives with different scaffolds that would allow establishing covalent interactions with the target. The proposed structures were optimised for better binding and drug\u2010like properties. Docking studies showed that some of the new compounds had improved binding scores over nafamostat. Physicochemical and ADME properties analysis indicated that most of the compounds exhibit favourable drug\u2010like properties except for a small number that showed poor solubility or absorption. Different synthetic pathways were designed and optimised for the preparation of the five families, and the 40 compounds obtained were fully characterised. Unfortunately, in cell\u2010based assays, none of the new compounds prepared effectively blocked SARS\u2010CoV\u20102 entry, suggesting that further optimisation is needed. Overall, the work presented expands the chemical space for targeting TMPRSS2 and provides valuable insights for future antiviral drug development.<\/jats:p>","DOI":"10.1002\/cmdc.70524","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:49:27Z","timestamp":1791870567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Searching for Novel COVID19 Treatments: Towards Covalent TMPRSS2 Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"given":"Marco","family":"Minneci","sequence":"first","affiliation":[{"name":"School of Chemistry TBSI Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Farka\u0161","sequence":"additional","affiliation":[{"name":"School of Chemistry TBSI Trinity College Dublin  Dublin 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