FigsharePub Date : 2018-03-19DOI: 10.1021/acs.jmedchem.7b01312.s001
Morane Le Hiress (4975352), Bernardin Akagah (4975349), Guillaume Bernadat (1525456), Ly Tu (4975355), Raphaël Thuillet (4975346), Alice Huertas (4975367), Carole Phan (4975358), Elie Fadel (471021), Gérald Simonneau (3727672), Marc Humbert (23466), Gaël Jalce (4975361), Christophe Guignabert (4975364)
{"title":"Design, Synthesis,nand Biological Activity of New <i>N</i>‑(Phenylmethyl)-benzoxazol-2-thionesnas MacrophagenMigration Inhibitory Factor (MIF) Antagonists: Efficacies in ExperimentalnPulmonary Hypertension","authors":"Morane Le Hiress (4975352), Bernardin Akagah (4975349), Guillaume Bernadat (1525456), Ly Tu (4975355), Raphaël Thuillet (4975346), Alice Huertas (4975367), Carole Phan (4975358), Elie Fadel (471021), Gérald Simonneau (3727672), Marc Humbert (23466), Gaël Jalce (4975361), Christophe Guignabert (4975364)","doi":"10.1021/acs.jmedchem.7b01312.s001","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.7b01312.s001","url":null,"abstract":"Macrophagenmigration inhibitory factor (MIF) is a key pleiotropicnmediator and a promising therapeutic target in cancer as well as innseveral inflammatory and cardiovascular diseases including pulmonarynarterial hypertension (PAH). Here, a novel series of <i>N</i>-(phenylmethyl)-benzoxazol-2-thiones <b>5</b>–<b>32</b> designed to target the MIF tautomerase active site wasnsynthesized and evaluated for its effects on cell survival. Investigationnof structure–activity relationship (SAR) particularly at then5-position of the benzoxazole core led to the identification of <b>31</b> that potently inhibits cell survival in DU-145 prostatencancer cells and pulmonary endothelial cells derived from patientsnwith idiopathic PAH (iPAH-ECs), two cell lines for which survivalnis MIF-dependent. Molecular docking studies helped to interpret initialnSAR related to MIF tautomerase inhibition and propose preferred bindingnmode for <b>31</b> within the MIF tautomerase active site. Interestingly,ndaily treatment with <b>31</b> started 2 weeks after a subcutaneousnmonocrotaline injection regressed established pulmonary hypertensionnin rats.","PeriodicalId":522888,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147905568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}