{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T22:15:04Z","timestamp":1776464104618,"version":"3.51.2"},"reference-count":40,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T00:00:00Z","timestamp":1643068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005902","name":"Institute for Clinical and Translational Research","doi-asserted-by":"publisher","award":["UL1TR003098"],"award-info":[{"award-number":["UL1TR003098"]}],"id":[{"id":"10.13039\/100005902","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Treatment options for human cytomegalovirus (CMV) remain limited and are associated with significant adverse effects and the selection of resistant CMV strains in transplant recipients and congenitally infected infants. Although most approved drugs target and inhibit the CMV DNA polymerase, additional agents with distinct mechanisms of action are needed for the treatment and prevention of CMV. In a large high throughput screen using our CMV-luciferase reporter Towne, we identified several unique inhibitors of CMV replication. Here, we synthesize and test in vitro 13 analogs of the original NCGC2955 hit (1). Analogs with no activity against the CMV-luciferase at 10 \u00b5M and 30 \u00b5M (2\u20136, 10\u201314) were removed from further analysis. Three analogs (7\u20139) inhibited CMV replication in infected human foreskin fibroblasts. The EC50 of (1) was 1.7 \u00b1 0.6 \u00b5M and 1.99 \u00b1 0.15 \u00b5M, based on luciferase and plaque assay, respectively. Compounds 7, 8, and 9 showed similar activities: the EC50 values of 7 were 0.21 \u00b1 0.06 \u00b5M (luciferase) and 0.55 \u00b1 0.06 (plaque), of 8: 0.28 \u00b1 0.06 \u00b5M and 0.42 \u00b1 0.07, and of 9: 0.30 \u00b1 0.05 \u00b5M (luciferase) and 0.35 \u00b1 0.07 (plaque). The CC50 for 7, 8, and 9 in non-infected human foreskin fibroblasts was &gt; 500\u00b5M, yielding a selectivity index of &gt;1500. Compounds 1, 7, and 8 were also tested in CMV-infected primary human hepatocytes and showed a dose\u2013response against CMV by luciferase activity and viral protein expression. None of the active compounds inhibited herpes simplex virus 1 or 2. Compounds 7 and 8 inhibited mouse CMV replication in vitro. Both inhibited CMV at late stages of replication; 7 reduced virus yield at all late time points, although not to the same degree as letermovir. Finally, the activity of analog 8 was additive with newly identified CMV inhibitors (MLS8969, NFU1827, MSL8554, and MSL8091) and with ganciclovir. Further structural activity development should provide promising anti-CMV agents for use in clinical studies.<\/jats:p>","DOI":"10.3390\/v14020234","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T20:42:26Z","timestamp":1643143346000},"page":"234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Synthesis and Anti-Cytomegalovirus Activity of Piperidine-4-Carboxamides"],"prefix":"10.3390","volume":"14","author":[{"given":"Xin","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Disease, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayan Kumar","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Disease, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F.","family":"Keyes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Forman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Meyers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5363-167X","authenticated-orcid":false,"given":"Ravit","family":"Arav-Boger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Disease, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1086\/508173","article-title":"Seroprevalence of Cytomegalovirus Infection in the United States, 1988\u20131994","volume":"43","author":"Staras","year":"2006","journal-title":"Clin. 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