{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:17:35Z","timestamp":1788383855247,"version":"build-2803163510"},"reference-count":61,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2015,5,16]],"date-time":"2015-05-16T00:00:00Z","timestamp":1431734400000},"content-version":"vor","delay-in-days":16,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SPP 1580"],"award-info":[{"award-number":["SPP 1580"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerische Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["CRSI33_130016"],"award-info":[{"award-number":["CRSI33_130016"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["0315834C"],"award-info":[{"award-number":["0315834C"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The causative agent of Legionnaires\u2019 disease, Legionella pneumophila, grows in environmental amoebae and mammalian macrophages within a distinct compartment, the \u2018Legionella-containing vacuole\u2019 (LCV). Intracellular bacteria are protected from many antibiotics, and thus are notoriously difficult to eradicate. To identify novel compounds that restrict intracellular bacterial replication, we previously developed an assay based on a coculture of amoebae and GFP-producing L. pneumophila. This assay was used to screen a pathway-based, highly diverse chemical library, referred to as the Sinergia library. In this work, we chose to focus on a group of 11 hit compounds, the majority of which originated from the query molecule CN585, a compound that targets the protein phosphatase calcineurin. Further studies on 78 related compound variants revealed crucial structural attributes, namely a triple-ring scaffold with a central triazine moiety, substituted in positions 3 and 5 by two piperidine or pyrrolidine rings, and in position 1 by an amine group bearing a single aliphatic chain moiety. The most effective compound, ZINC00615682, inhibited intracellular replication of L. pneumophila with an IC50 of approximately 20 nM in Acanthamoeba castellanii and slightly less efficiently in Dictyostelium discoideum or macrophages. Pharmacological and genetic attempts to implicate calcineurin in the intracellular replication of L. pneumophila failed. Taken together, these results show that the amoebae-based screen and structure\u2013activity relationship analysis is suitable for the identification of novel inhibitors of the intracellular replication of L. pneumophila. The most potent compound identified in this study targets (an) as yet unidentified host factor(s).<\/jats:p>","DOI":"10.1021\/acsinfecdis.5b00002","type":"journal-article","created":{"date-parts":[[2015,4,30]],"date-time":"2015-04-30T18:19:33Z","timestamp":1430417973000},"page":"327-338","source":"Crossref","is-referenced-by-count":13,"title":["Amoebae-Based Screening Reveals a Novel Family of\nCompounds Restricting Intracellular\n                    <i>Legionella pneumophila<\/i>"],"prefix":"10.1021","volume":"1","author":[{"given":"Christopher F.","family":"Harrison","sequence":"first","affiliation":[{"name":"Ludwig-Maximilians University Munich , , ,","place":["Munich, Germany, 80336"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianpaolo","family":"Chiriano","sequence":"additional","affiliation":[{"name":"University of Geneva and University of Lausanne , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Finsel","sequence":"additional","affiliation":[{"name":"Ludwig-Maximilians University Munich , , ,","place":["Munich, Germany, 80336"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Manske","sequence":"additional","affiliation":[{"name":"Ludwig-Maximilians University Munich , , ,","place":["Munich, Germany, 80336"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Ludwig-Maximilians University Munich , , ,","place":["Munich, Germany, 80336"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Steiner","sequence":"additional","affiliation":[{"name":"University of Zurich , , Gloriastrasse 30\/32 , ,","place":["Zurich, Switzerland, 8006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Kranjc","sequence":"additional","affiliation":[{"name":"University of Geneva and University of Lausanne , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ophelie","family":"Patthey-Vuadens","sequence":"additional","affiliation":[{"name":"University of Geneva and University of Lausanne , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se\u0301bastien","family":"Kicka","sequence":"additional","affiliation":[{"name":"University of Geneva , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentin","family":"Trofimov","sequence":"additional","affiliation":[{"name":"University of Geneva , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajer","family":"Ouertatani-Sakouhi","sequence":"additional","affiliation":[{"name":"University of Geneva , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Soldati","sequence":"additional","affiliation":[{"name":"University of Geneva , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Scapozza","sequence":"additional","affiliation":[{"name":"University of Geneva and University of Lausanne , , ,","place":["Geneva, Switzerland, 1211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Hilbi","sequence":"additional","affiliation":[{"name":"Ludwig-Maximilians University Munich , , ,","place":["Munich, Germany, 80336"]},{"name":"University of Zurich , , Gloriastrasse 30\/32 , ,","place":["Zurich, Switzerland, 8006"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2015,4,30]]},"reference":[{"key":"2026090216312143700_cit1","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1111\/j.1758-2229.2011.00247.x","article-title":"Legionella spp. outdoors: colonization, communication and\npersistence","volume":"3","author":"Hilbi","year":"2011","journal-title":"Environ. 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Med.\nChem."},{"key":"2026090216312143700_cit25","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/1478-811X-7-25","article-title":"Novel inhibitors\nof the calcineurin\/NFATc hub - alternatives to CsA and FK506?","volume":"7","author":"Sieber","year":"2009","journal-title":"Cell Commun. Signaling"},{"key":"2026090216312143700_cit26","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1074\/jbc.M109.024844","article-title":"The novel calcineurin\ninhibitor CN585 has potent immunosuppressive properties in stimulated\nhuman T cells","volume":"285","author":"Erdmann","year":"2010","journal-title":"J. Biol. 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Sin."},{"key":"2026090216312143700_cit30","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1038\/ncb883","article-title":"Legionella phagosomes intercept vesicular\ntraffic from endoplasmic reticulum exit sites","volume":"4","author":"Kagan","year":"2002","journal-title":"Nat. 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