2-(5-ethylthiophen-2-yl)-6-fluoro-3-(4-fluorobenzyl)-2,3-dihydroquinazolin-4(1H)-one | 1542098-94-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-(5-ethylthiophen-2-yl)-6-fluoro-3-(4-fluorobenzyl)-2,3-dihydroquinazolin-4(1H)-one
• 英文别名: DHQZ 36；2-(5-Ethylthiophene-2-yl)-6-fluoro-3-(4-fluorobenzyl)-2,3-dihydroquinazoline-4(1H)-one；2-(5-ethylthiophen-2-yl)-6-fluoro-3-[(4-fluorophenyl)methyl]-1,2-dihydroquinazolin-4-one
• CAS: 1542098-94-1
• 化学式: C₂₁H₁₈F₂N₂OS
• 分子量: 384.45
• InChiKey: SVXVTSKHYHQIPJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  60.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对氟苄胺 在 4-二甲氨基吡啶 、 palladium 10% on activated carbon 、 甲酸铵 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 scandium tris(trifluoromethanesulfonate) 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 19.0h， 生成 2-(5-ethylthiophen-2-yl)-6-fluoro-3-(4-fluorobenzyl)-2,3-dihydroquinazolin-4(1H)-one
  参考文献：
  名称：

  Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections

  摘要：

  在受感染的哺乳动物细胞中，利什曼原虫寄生虫存在于称为寄生泡（LPV）的特殊隔室中。我们之前已经表明，Retro-2（一种新型小型逆行途径抑制剂的成员）在实验性 L. mexicana sp. 过程中导致 LPV 大小减小和寄生虫数量减少。感染。本研究的目的是确定Retro-2cycl的结构类似物是否在抑制逆行途径依赖性现象（即多瘤病毒引起的多瘤病毒细胞感染和细胞内志贺毒素贩运）方面具有更优异的效力，也比Retro-2cycl的结构类似物更有效。控制利什曼原虫感染的母体化合物。除了对 LPV 发育的影响外，我们还发现，Retro-2cycl 的两种优化类似物 DHQZ 36 和 DHQZ 36.1 可限制巨噬细胞中的亚马逊利什曼原虫感染，EC50 分别为 13.63+/-2.58μM 和 10.57+/-2.66μM ，显着低于Retro-2cycl 40.15μM的EC50。此外，这些类似物在 LPS 激活后逆转了利什曼原虫诱导的受感染细胞释放 IL-6 的抑制。此外，我们表明，与静态利什曼原虫的 Retro-2cycl 相比，类似物可以杀死无菌培养物中的利什曼原虫寄生虫，这是任何治疗利什曼原虫感染的药物的理想属性。这些研究共同验证并扩展了已发表的 Retro-2cycl 结构-活性关系分析。

  DOI：

  10.1371/journal.pntd.0005556

文献信息

• [EN] COMPOUNDS FOR THE TREATMENT AND PREVENTION OF INFECTIONS<br/>[FR] COMPOSÉS DESTINÉS AU TRAITEMENT ET À LA PRÉVENTION D'INFECTIONS
  申请人：UNIV BROWN

  公开号：WO2014014814A1

  公开（公告）日：2014-01-23

  Provided herein are compounds of Formula (I) or (II): (I) (II) harmaceutically acceptable salts, tautomers, prodrugs, and stereoisomers thereof, and pharmaceutical compositions thereof, wherein X, RN, R1,R3,R4, p, and m are as defined herein. Such compounds and compositions have been found useful in the treatment or prevention of viral infections, e.g., polyomaviral infections, and are further envisioned useful in treatment or prevention of other pathogenic conditions associated with endosomal trafficking. Methods of treating or preventing an infection by a pathogen secreting an AB5 toxin is also contemplated.

  本文提供了化合物的公式(I)或(II)：(I) (II) 其药用可接受的盐、互变异构体、前药和立体异构体，以及药物组合物，其中X、RN、R1、R3、R4、p和m如本文所定义。已发现这些化合物和组合物在治疗或预防病毒感染，例如聚病毒感染方面具有用处，并且进一步被认为在治疗或预防与溶酶体运输相关的其他病原体条件方面有用。还考虑了通过治疗或预防分泌AB5毒素的病原体感染的方法。
• Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses
  作者：Daniel W. Carney、Christian D.S. Nelson、Bennett D. Ferris、Julia P. Stevens、Alex Lipovsky、Teymur Kazakov、Daniel DiMaio、Walter J. Atwood、Jason K. Sello

  DOI：10.1016/j.bmc.2014.06.053

  日期：2014.9

  Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of polyomavirus-induced nephropathy and hemorrhagic cystitis. Human papillomavirus type 16, another non-enveloped DNA virus, is associated with the development of cancers in tissues like the uterine cervix and oropharynx. Currently, there are no approved drugs or vaccines to treat or prevent polyomavirus infections. We recently discovered that the small molecule Retro-2(cycl), an inhibitor of host retrograde trafficking, blocked infection by several human and monkey polyomaviruses. Here, we report diversity-oriented syntheses of Retro-2(cycl) and evaluation of the resulting analogs using an assay of human cell infections by JC polyomavirus. We defined structure-activity relationships and also discovered analogs with significantly improved potency as suppressors of human polyoma- and papillomavirus infection in vitro. Our findings represent an advance in the development of drug candidates that can broadly protect humans from non-enveloped DNA viruses and toxins that exploit retrograde trafficking as a means for cell entry.
• COMPOUNDS FOR THE TREATMENT AND PREVENTION OF INFECTIONS
  申请人：Brown University

  公开号：US20150166517A1

  公开（公告）日：2015-06-18

  Provided herein are compounds of Formula (I) or (II): (I) (II) pharmaceutically acceptable salts, tautomers, prodrugs, and stereoisomers thereof, and pharmaceutical compositions thereof, wherein X, R N , R 1 , R 3 , R 4 , p, and m are as defined herein. Such compounds and compositions have been found useful in the treatment or prevention of viral infections, e.g., polyomaviral infections, and are further envisioned useful in treatment or prevention of other pathogenic conditions associated with endosomal trafficking. Methods of treating or preventing an infection by a pathogen secreting an AB 5 toxin is also contemplated.
• US9695156B2
  申请人：——

  公开号：US9695156B2

  公开（公告）日：2017-07-04
• Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections
  作者：Evan Craig、Charles-Eugene Huyghues-Despointes、Chun Yu、Emma L. Handy、Jason K. Sello、Peter E. Kima

  DOI：10.1371/journal.pntd.0005556

  日期：——

  In infected mammalian cells, Leishmania parasites reside within specialized compartments called parasitophorous vacuoles (LPVs). We have previously shown that Retro-2, a member of a novel class of small retrograde pathway inhibitors caused reduced LPV sizes and lower parasite numbers during experimental L. mexicana sp. infections. The purpose of this study was to determine if structural analogs of Retro-2cycl reported to have superior potency in the inhibition of retrograde pathway-dependent phenomena (i.e., polyomavirus cellular infection by polyomavrius and Shiga toxin trafficking in cells) are also more effective than the parent compound at controlling Leishmania infections. In addition to their effects on LPV development, we show that two optimized analogs of Retro-2cycl, DHQZ 36 and DHQZ 36.1 limit Leishmania amazonensis infection in macrophages at EC50 of 13.63+/-2.58μM and10.57+/-2.66μM, respectively, which is significantly lower than 40.15μM the EC50 of Retro-2cycl. In addition, these analogs caused a reversal in Leishmania induced suppression of IL-6 release by infected cells after LPS activation. Moreover, we show that in contrast to Retro-2cycl that is Leishmania static, the analogs can kill Leishmania parasites in axenic cultures, which is a desirable attribute for any drug to treat Leishmania infections. Together, these studies validate and extend the published structure-activity relationship analyses of Retro-2cycl.

  在受感染的哺乳动物细胞中，利什曼原虫寄生虫存在于称为寄生泡（LPV）的特殊隔室中。我们之前已经表明，Retro-2（一种新型小型逆行途径抑制剂的成员）在实验性 L. mexicana sp. 过程中导致 LPV 大小减小和寄生虫数量减少。感染。本研究的目的是确定Retro-2cycl的结构类似物是否在抑制逆行途径依赖性现象（即多瘤病毒引起的多瘤病毒细胞感染和细胞内志贺毒素贩运）方面具有更优异的效力，也比Retro-2cycl的结构类似物更有效。控制利什曼原虫感染的母体化合物。除了对 LPV 发育的影响外，我们还发现，Retro-2cycl 的两种优化类似物 DHQZ 36 和 DHQZ 36.1 可限制巨噬细胞中的亚马逊利什曼原虫感染，EC50 分别为 13.63+/-2.58μM 和 10.57+/-2.66μM ，显着低于Retro-2cycl 40.15μM的EC50。此外，这些类似物在 LPS 激活后逆转了利什曼原虫诱导的受感染细胞释放 IL-6 的抑制。此外，我们表明，与静态利什曼原虫的 Retro-2cycl 相比，类似物可以杀死无菌培养物中的利什曼原虫寄生虫，这是任何治疗利什曼原虫感染的药物的理想属性。这些研究共同验证并扩展了已发表的 Retro-2cycl 结构-活性关系分析。