KKL-35 | 865285-29-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: KKL-35
• 英文别名: 4-chloro-N-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzamide；4-chloro-N-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]benzamide
• CAS: 865285-29-6
• 化学式: C₁₅H₉ClFN₃O₂
• 分子量: 317.707
• InChiKey: ZIICPNCCHIUJSX-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO：可溶5mg/mL，澄清（加热）

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  68
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P264,P270,P301+P312,P330,P501
• 危险性描述：
  H302

制备方法与用途

生物活性

KKL-35 抑制 trans-translation tagging 反应，其 IC50 为 0.9 μM。它具有广谱抗生素活性。

靶点

IC50: 0.9 µM (trans-translation tagging 反应)

体外研究

KKL-35 展现了广泛的抗生素活性。它能阻止 B. anthracis 和 M. smegmatis 的生长，最小抑制浓度（MIC）值低于 6 µM。KKL-35 在某些步骤之前抑制 trans-translation，并阻止标记蛋白的水解。它还抑制 DHFR-ns 标记。在最高浓度 KKL-35 反应中产生大量未标记的 DHFR，表明 KKL-35 不抑制翻译。KKL-35 能够以 6 µM 的 MIC 值阻止 S. flexneri 的生长，并且加入 KKL-35 到 S. flexneri 生长培养中会停止其生长。在表达 ArfA 并删除 ssrA 的 S. flexneri 突变株中，添加 KKL-35 对生存率或生长速率影响甚微。另外，KKL-35 能够以 0.3 µM 的 MIC 值抑制缺乏小分子外排的 E. coli ∆tolC 的生长。

体内研究

证据表明，KKL-35 在体内的效果是由其对 trans-translation 释放非终止翻译复合物的抑制作用引起的。它能够抑制 trans-translation 并阻止需要 trans-translation 的 S. flexneri 突变株生长。遗传学和药理学实验支持这种抑制与生长之间的相关性，证明替代机制可以缓解 KKL-35 引起的增长抑制现象。

反应信息

• 作为产物：
  描述：

  (E)-2-(4-fluorobenzylidene)hydrazine-1-carboxamide 在 吡啶 、 sodium acetate 、 溶剂黄146 作用下， 反应 19.0h， 生成 KKL-35
  参考文献：
  名称：

  Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain

  摘要：

  Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2+/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1 /AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2+/calmodulin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2+/calmodulin-stimulated AC1- and AC8 CAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.11.036

文献信息

• [EN] METABOLICALLY STABLE N-ACYLAMINOOXADIAZOLES USEFUL AS ANTIBACTERIAL AGENTS<br/>[FR] N-ACYLAMINOOXADIAZOLES STABLES D'UN POINT DE VUE MÉTABOLIQUE UTILES EN TANT QU'AGENTS ANTIBACTÉRIENS
  申请人：MICROBIOTIX INC

  公开号：WO2019040404A1

  公开（公告）日：2019-02-28

  The present invention is related to the development of therapeutics and prophylactics for the treatment and/or prevention of bacterial infections in humans and other mammals. A new class of small molecules is disclosed that inhibits the bacterial trans-translation/ribosome rescue mechanism and thus blocks infection of host cells by bacteria. Also disclosed are methods of using the small molecule inhibitors in the treatment/prevention of bacterial infections.

  本发明涉及开发治疗和预防人类和其他哺乳动物细菌感染的治疗和/或预防药物。公开了一类新型小分子，它抑制细菌的转运转译/核糖体救援机制，从而阻止细菌感染宿主细胞。还公开了使用这些小分子抑制剂治疗/预防细菌感染的方法。
• trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo
  作者：Zachary D. Aron、Atousa Mehrani、Eric D. Hoffer、Kristie L. Connolly、Pooja Srinivas、Matthew C. Torhan、John N. Alumasa、Mynthia Cabrera、Divya Hosangadi、Jay S. Barbor、Steven C. Cardinale、Steven M. Kwasny、Lucas R. Morin、Michelle M. Butler、Timothy J. Opperman、Terry L. Bowlin、Ann Jerse、Scott M. Stagg、Christine M. Dunham、Kenneth C. Keiler

  DOI：10.1038/s41467-021-22012-7

  日期：——

  Bacterial ribosome rescue pathways that remove ribosomes stalled on mRNAs during translation have been proposed as novel antibiotic targets because they are essential in bacteria and are not conserved in humans. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans-translation, the main ribosome rescue pathway in bacteria. Here, we report optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Single particle cryogenic-EM studies of non-stop ribosomes show that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein bL27, suggesting a novel mechanism for specific inhibition of trans-translation by these molecules. These results show that trans-translation is a viable therapeutic target and reveal a new conformation within the bacterial ribosome that may be critical for ribosome rescue pathways.

  标题：摘要 细菌核糖体救援途径被提出作为新型抗生素靶点，因为它们在细菌中是必不可少的，而在人类中并不保守。我们先前报道了一类选择性抑制细菌主要核糖体救援途径——转-翻译的酰胺氧代唑家族的发现。在这里，我们报告了对酰胺氧代唑的药代动力学和抗生素性能的优化，产生了MBX-4132，它在小鼠中经过一次口服剂量即可清除多药耐药的淋病奈瑟氏菌感染。非停止核糖体的单粒子冷冻电镜研究显示，酰胺氧代唑结合到靠近肽基转移中心的独特位点，并显著改变核糖体蛋白bL27的构象，表明这些分子通过一种新型机制特异性抑制转-翻译。这些结果表明转-翻译是一个可行的治疗靶点，并揭示了细菌核糖体内可能对核糖体救援途径至关重要的新构象。
• ADENYLYL CYCLASE INHIBITORS FOR CHRONIC PAIN AND OPIOID DEPENDENCE
  申请人：Purdue Research Foundation

  公开号：US20190002418A1

  公开（公告）日：2019-01-03

  This present application disclosed a series of selective adenylyl cyclase 1 (AC1) inhibitors as a pain therapeutic. Those compounds may provide an effective method of treatment for chronic/inflammatory pain. Those compounds may also prevent opioid dependence and/or reduce opioid dependence. Both method and composition matters are within the scope of this invention.

  本申请公开了一系列选择性腺苷酸环化酶1（AC1）抑制剂作为疼痛治疗的药物。这些化合物可能提供一种有效的治疗慢性/炎性疼痛的方法。这些化合物还可以预防阿片类药物依赖和/或减少阿片类药物依赖。该发明涉及方法和组合物两个方面。
• Adenylyl cyclase inhibitors for chronic pain and opioid dependence
  申请人：Purdue Research Foundation

  公开号：US10457653B2

  公开（公告）日：2019-10-29

  This present application disclosed a series of selective adenylyl cyclase 1 (AC1) inhibitors, compounds having a formula or a pharmaceutically acceptable salt thereof, as a pain therapeutic. Those compounds may provide an effective method of treatment for chronic/inflammatory pain. Those compounds may also prevent opioid dependence and/or reduce opioid dependence. Both method and composition matters are within the scope of this invention.

  本申请公开了一系列选择性腺苷酸环化酶 1（AC1）抑制剂，这些化合物的化学式为 或其药学上可接受的盐，作为疼痛治疗剂。这些化合物可为慢性/炎症性疼痛提供有效的治疗方法。这些化合物还可以预防阿片类药物依赖和/或减少阿片类药物依赖。方法和组合物均属于本发明的范围。
• METHODS FOR TREATING CHRONIC PAIN AND OPIOID DEPENDENCE USING ADENYLYL CYCLASE INHIBITORS
  申请人：Purdue Research Foundation

  公开号：US20200031785A1

  公开（公告）日：2020-01-30

  This present application disclosed a method for the treatment of treating pain, opioid dependence, alcohol use disorder or autism comprising the step of administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and one or more carriers, diluents, or excipients. Those compounds are selective adenylyl cyclase 1 (AC1) inhibitors, which may provide an effective method of treatment for chronic/inflammatory pain, and prevent opioid dependence and/or reduce opioid dependence.