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Starting from antifungal lead compound haloperidol that was identified by drug repurposing, a series of novel benzocyclane derivatives were designed, synthesized, and assayed. Several compounds showed improved antifungal potency and broader antifungal spectra. Particularly, compound B10 showed good inhibitory activities against a variety of fungal pathogens and was proven to be an inhibitor of several virulence factors important for drug resistance. In the in vivo cryptococcosis and candidiasis models, compound B10 could effectively reduce the brain fungal burden of Cryptococcus neoformans and synergize with fluconazole to treat resistant Candida albicans infections. Preliminary antifungal mechanism studies revealed that compound B10 regained cell membrane damage and down-regulated the overexpression of ERG11 and MDR1 genes when used in combination with fluconazole. Taken together, haloperidol derivative B10 represents a promising lead compound for the development of a new generation of antifungal agents.<\/jats:p>","DOI":"10.1021\/acsinfecdis.9b00197","type":"journal-article","created":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T20:10:38Z","timestamp":1569355838000},"page":"768-786","source":"Crossref","is-referenced-by-count":48,"title":["Drug Repurposing of Haloperidol: Discovery of New\nBenzocyclane Derivatives as Potent Antifungal Agents against Cryptococcosis\nand Candidiasis"],"prefix":"10.1021","volume":"6","author":[{"given":"Changjin","family":"Ji","sequence":"first","affiliation":[{"name":"East China University of Science & Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]},{"name":"Second Military Medical University , , 325 Guohe Road , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Liu","sequence":"additional","affiliation":[{"name":"Second Military Medical University , , 325 Guohe Road , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Tu","sequence":"additional","affiliation":[{"name":"Second Military Medical University , , 325 Guohe Road , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang","family":"Li","sequence":"additional","affiliation":[{"name":"East China University of Science & Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]},{"name":"Second Military Medical University , , 325 Guohe Road , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiyan","family":"Han","sequence":"additional","affiliation":[{"name":"Second Military Medical University , , 325 Guohe Road , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7521-8798","authenticated-orcid":true,"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"East China University of Science & Technology , , 130 Meilong Road , ,","place":["Shanghai, People\u2019s Republic of China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-804X","authenticated-orcid":true,"given":"Chunquan","family":"Sheng","sequence":"additional","affiliation":[{"name":"Second Military Medical University , , 325 Guohe Road , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,9,24]]},"reference":[{"key":"2026081806113663100_cit1","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nrd.2017.46","article-title":"The antifungal\npipeline: a reality check","volume":"16","author":"Perfect","year":"2017","journal-title":"Nat. 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