Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5–32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure–activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent. Molecular docking studies helped to interpret initial SAR related to MIF tautomerase inhibition and propose preferred binding mode for 31 within the MIF tautomerase active site. Interestingly, daily treatment with 31 started 2 weeks after a subcutaneous monocrotaline injection regressed established pulmonary hypertension in rats.

中文翻译：

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新的N-（苯甲基）-苯并恶唑-2-硫酮作为巨噬细胞迁移抑制因子（MIF）拮抗剂的设计，合成和生物活性：实验性肺动脉高压的功效。

巨噬细胞迁移抑制因子（MIF）是癌症的关键多效性介质和有希望的治疗靶标，并且在包括肺动脉高压（PAH）在内的多种炎性和心血管疾病中也是如此。在这里，合成了一系列针对MIF互变异构酶活性位点的N-（苯甲基）-苯并恶唑-2-硫酮5 – 32系列，并评估了其对细胞存活的影响。研究结构-活性关系（SAR），特别是在苯并恶唑核的5位上，鉴定出31它有效地抑制了来自特发性PAH（iPAH-ECs）患者的DU-145前列腺癌细胞和肺内皮细胞的细胞存活，这两种细胞系均依赖MIF存活。分子对接研究有助于解释与MIF互变异构酶抑制作用有关的初始SAR，并提出了MIF互变异构酶活性位点中31种的首选结合方式。有趣的是，皮下注射久效林注射使大鼠已确立的肺动脉高压消退后的两周，开始用31进行每日治疗。