6-(bromomethyl)-5-(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine | 1486553-97-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-(bromomethyl)-5-(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine
• 英文别名: [6-(bromomethyl)-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl]methanol
• CAS: 1486553-97-2
• 化学式: C₁₂H₁₆BrNO₃
• 分子量: 302.168
• InChiKey: GDLOQQHVWVHXSA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.42
• 重原子数：
  17.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  51.58
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  6-(bromomethyl)-5-(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine 、 特比萘芬 以 乙腈 为溶剂， 反应 24.0h， 以67%的产率得到5-(hydroxymethyl)-6-(methylene(N-methyl-N-((E)-6,6-dimethylhept-2-en-4-yn1-yl)-N-(naphthalen-1-ylmethyl)aminium))- 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridinium bromide
  参考文献：
  名称：

  Targeting pathogenic fungi, bacteria and fungal-bacterial biofilms by newly synthesized quaternary ammonium derivative of pyridoxine and terbinafine with dual action profile

  摘要：

  Many pathogenic bacteria and microscopic fungi form rigid polymicrobial biofilms this way enhancing their resistant to treatment. A series of novel pyridoxine-based quaternary ammonium derivatives of terbinafine characterized by both antifungal and antibacterial activities was designed. The leading compound named KFU-127 exhibits promising antifungal and antibacterial activities against various bacteria and micromycetes in both planktonic and biofilm-embedded forms demonstrating MIC values comparable with those of conventional antifungals and antimicrobials. Similar to other antiseptics like benzalkonium chloride and miramistin, KFU-127 is considerably toxic for eukaryotic cells that limits is application to topical treatment options. On the other hand, KFU-127 reduces the number of viable biofilm-embedded bacteria and C. albicans by 3 orders of magnitude at concentrations 2-4 times lower than those of reference drugs and successfully eradicates S. aureus-C. albicans mixed biofilms. The mechanism of antimicrobial action of KFU-127 is bimodal including both membrane integrity damage and pyridoxal-dependent enzymes targeting. We expect that this bilateral mechanism would result in lower rates of resistance development in both fungal and bacterial pathogens. Taken together, our data suggest KFU-127 as a new promising broad spectrum topical antimicrobial capable of one-shot targeting of bacterial and fungal-bacterial biofilms.

  DOI：

  10.1016/j.bioorg.2020.104306
• 作为产物：
  描述：

  2,3,4-tris(hydroxymethyl)-6-methylpyridin-5-ol 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 24.5h， 生成 6-(bromomethyl)-5-(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine
  参考文献：
  名称：

  吡ido醇双-盐：结构与抗菌活性之间的关系

  摘要：

  合成了一系列基于吡ido醇的23种新型双salts盐，并对其体外抗菌活性进行了评估。所有化合物对革兰氏阴性菌均无活性，并且对革兰氏阳性菌表现出结构依赖性活性。随着乙缩醛碳原子上链长的增加，抗菌活性增强，顺序为n -Pr> Et> Me。烷基链的长度和支链的进一步增加导致抗菌活性降低。5,6-双（三苯基膦基（甲基）-2,2,2,8-三甲基-4 H- [1,3]-二氧[4,5- c ]吡啶二氯化物（化合物1）与正丁基，m-甲苯基或对甲苯基以及含溴化物的化合物1中的氯阴离子（化合物14a）将其对金黄色葡萄球菌和表皮葡萄球菌的活性提高了5倍（MIC = 1–1.25μg/ ml）。但实际上在所有情况下，化合物1的化学修饰都导致其对HEK-293细胞的毒性增加。唯一的例外是化合物5,6-双[三丁基膦基（甲基）]-2,2,8-三甲基-4 H- [1,3]二氧杂[4,5- c ]吡啶二氯化物（10a），

  DOI：

  10.1016/j.bmc.2013.09.056

文献信息

• Fluconazole-Pyridoxine Bis-Triazolium Compounds with Potent Activity against Pathogenic Bacteria and Fungi Including Their Biofilm-Embedded Forms
  作者：Marsel R. Garipov、Roman S. Pavelyev、Svetlana A. Lisovskaya、Elena V. Nikitina、Airat R. Kayumov、Alina E. Sabirova、Oksana V. Bondar、Albina G. Malanyeva、Alexander M. Aimaletdinov、Alfia G. Iksanova、Konstantin V. Balakin、Yurii G. Shtyrlin

  DOI：10.1155/2017/4761650

  日期：——

  staphylococci and Escherichia coli. While no biofilm structure destruction occurred, all compounds were able to diffuse into the matrix and reduce the number of colony-forming units by three orders of magnitude at 16 × MBC. The leading compound was significantly less toxic than miramistin and benzalkonium chloride and more toxic than the reference antifungal drugs. The obtained results make the described chemotype

  通过氟康唑与吡哆醇基合成中间体的反应，合成了两种新型季铵盐，即氟康唑和吡哆醇的双三唑鎓衍生物。领先的化合物在体外表现出明显的抗真菌和抗菌活性，与参考抗真菌药（氟康唑、特比萘芬）和抗菌/防腐剂（米拉米斯汀、苯扎氯铵）相当或超过。与许多抗菌剂相比，主要化合物对生物膜嵌入的葡萄球菌和大肠杆菌也有活性。虽然没有发生生物膜结构破坏，但所有化合物都能够扩散到基质中，并在 16 × MBC 时将集落形成单位的数量减少三个数量级。领先化合物的毒性明显低于米拉米斯汀和苯扎氯铵，而毒性高于参考抗真菌药物。获得的结果使所描述的化学型成为开发新的广谱抗菌疗法的有希望的起点，对真菌和细菌病原体（包括其生物膜嵌入形式）具有强大的影响。
• Synthesis and Antibacterial Activity of Novel Quaternary Ammonium Pyridoxine Derivatives
  作者：Nikita Shtyrlin、Sergey Sapozhnikov、Sergey Koshkin、Alfiya Iksanova、Arthur Sabirov、Airat Kayumov、Aliya Nureeva、Marina Zeldi、Yurii Shtyrlin

  DOI：10.2174/1573406411666150504122930

  日期：2015.9.22

  A series of 26 quaternary ammonium pyridoxine derivatives were synthesized and their cytotoxicity and antibacterial activities against clinically relevant bacterial strains were tested in vitro. The antibacterial activity of mono-ammonium salts increased with the rise of the lipophilicity and compound 3,3,5-trimethyl-8,8-dioctyl-1,7,8,9-tetrahydro-[1,3]dioxino[5,4-d]pyrrolo[3,4-b]pyridin-8- ium chloride (2d) reaches a maximum among them. Bis-ammonium salt of pyridoxine 4 with two dimethyloctylamine groups also demonstrated high antibacterial activity despite lower lipophilicity. The results of MTT assay indicated that HEK 293 cells were more sensitive than HSF to quaternary ammonium pyridoxine derivatives. Compounds 2d and 4 did not induce the damage of the DNA and might be of interest in the development of new antimicrobials.

  合成了一系列26个季铵盐吡哆醇衍生物，并在体外测试了它们对临床相关细菌菌株的细胞毒性和抗菌活性。单季铵盐的抗菌活性随着亲脂性的增加而增强，其中3,3,5-三甲基-8,8-二辛基-1,7,8,9-四氢-[1,3]二氧杂环[5,4-d]吡咯[3,4-b]吡啶-8-氯化物（2d）的抗菌活性达到最高。含有两个二甲基辛胺基团的吡哆醇双季铵盐4虽然亲脂性较低，但也表现出较高的抗菌活性。MTT实验结果表明，HEK 293细胞对季铵盐吡哆醇衍生物的敏感性高于HSF细胞。化合物2d和4不会引起DNA损伤，可能在开发新型抗菌药物方面具有研究价值。
• Synthesis and biological evaluation of fluoroquinolones containing a pyridoxine derivatives moiety
  作者：Nikita V. Shtyrlin、Airat R. Kayumov、Maria N. Agafonova、Marsel R. Garipov、Alina E. Gatina、Mikhail V. Pugachev、Elena S. Bulatova、Denis Y. Grishaev、Alfiya G. Iksanova、Rail M. Khaziev、Ilnur M. Ganiev、Aleksandr M. Aimaletdinov、Oleg I. Gnezdilov、Yurii G. Shtyrlin

  DOI：10.1016/j.ejmech.2023.115798

  日期：2023.12

  We report herein the design, synthesis and biological evaluation of series of 7-substituted fluoroquinolones with pyridoxine derivatives. In vitro screening of antibacterial activity and toxicity of 39 synthesized fluoroquinolones defined compounds 7 and 28 as lead compounds for further investigations. On various clinical isolates lead compounds 7 and 28 exhibited antibacterial activity comparable

  我们在此报告了一系列带有吡哆醇衍生物的7-取代氟喹诺酮类药物的设计、合成和生物学评价。对 39 种合成的氟喹诺酮类药物的抗菌活性和毒性进行了体外筛选，确定化合物7和28作为先导化合物进行进一步研究。在各种临床分离株上，先导化合物7和28表现出与参考氟喹诺酮类药物相当的抗菌活性。在 SOS-chromotest 中尚未观察到这些化合物的致突变作用。化合物7对小鼠（LD 50  > 2000 mg/kg，口服）和大鼠（LD 50 > 2000 mg/kg，口服）体内无毒 。化合物28毒性更大（LD 50  = 474 mg/kg，口服，小鼠）。此外，在葡萄球菌败血症的小鼠模型中，与环丙沙星相比，化合物7显示出更高的体内功效。总的来说，所描述的活性化合物是临床前试验的有前途的候选化合物。