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Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10\u201312 triggered potential TMPRSS2 inhibition with low micromolar IC50 concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC50 value of 10.87 \u00b5M, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.<\/jats:p>","DOI":"10.3390\/v15051171","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T02:20:13Z","timestamp":1684203613000},"page":"1171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-6281","authenticated-orcid":false,"given":"Ahmed H. E.","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3962-6409","authenticated-orcid":false,"given":"Selwan M.","family":"El-Sayed","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3731-1702","authenticated-orcid":false,"given":"Mizuki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Gohda","sequence":"additional","affiliation":[{"name":"Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehisa","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikako","family":"Shirouzu","sequence":"additional","affiliation":[{"name":"Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-ichiro","family":"Inoue","sequence":"additional","affiliation":[{"name":"Infection and Advanced Research Center (UTOPIA), The University of Tokyo Pandemic Preparedness, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem M. A.","family":"Mansour","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abtin","family":"Anvari","sequence":"additional","affiliation":[{"name":"Master of Pharmaceutical Sciences Program, California Northstate University, 9700 W Taron Dr., Elk Grove, CA 95757, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelbasset A.","family":"Farahat","sequence":"additional","affiliation":[{"name":"Master of Pharmaceutical Sciences Program, California Northstate University, 9700 W Taron Dr., Elk Grove, CA 95757, USA"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.tmrv.2020.02.003","article-title":"Coronavirus Disease 2019: Coronaviruses and Blood Safety","volume":"34","author":"Chang","year":"2020","journal-title":"Transfus. 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