5,6-bis(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine | 1243585-27-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5,6-bis(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine
• 英文别名: 5,6-Bis(hydroxymethyl)-2,2,8-trimethyl-4h-[1,3]dioxino[4,5-c]pyridine；[6-(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl]methanol
• CAS: 1243585-27-4
• 化学式: C₁₂H₁₇NO₄
• 分子量: 239.271
• InChiKey: LKKSHKRUYVZLIB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  71.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5,6-bis(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine 在 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 0.5h， 以55%的产率得到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
• 作为产物：
  描述：

  6-(hydroxymethyl)-3,3,8-trimethyl-1,5-dihydro-[1,3] dioxepino [5,6-c] pyridin-9-ol 在 盐酸 、 2,2-二甲氧基丙烷 、 丙酮 作用下， 反应 30.0h， 以64%的产率得到5,6-bis(hydroxymethyl)-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine
  参考文献：
  名称：

  Theoretical and experimental study on cyclic 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-5-ol acetonides

  摘要：

  Methods for the preparation of three cyclic 2,3,4-tris(hydroxymethyl)-6-methylpyridin-5-ol acetonides have been developed by variation of the reaction conditions. The six-membered acetonide turned out to be thermodynamically more stable than the seven-membered acetonide and bis-acetonide. The experimental data were consistent with the results of quantum-chemical calculations. The structure of the isolated compounds was proved by X-ray analysis.

  DOI：

  10.1134/s1070428010040202

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 of novel 6-substituted sulfur-containing derivatives of pyridoxine
  作者：Nikita V. Shtyrlin、Roman S. Pavelyev、Mikhail V. Pugachev、Lubov P. Sysoeva、Rashid Z. Musin、Yurii G. Shtyrlin

  DOI：10.1016/j.tetlet.2012.05.086

  日期：2012.8

  An efficient synthesis of novel 6-substituted derivatives of pyridoxine was achieved. The reactions of various thiols with mono-, bis-, and tris(сhlorine) derivatives of 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-5-ol (6-hydroxymethylpyridoxine) gave sulfur-containing derivatives of pyridoxine.

  有效合成了吡ido醇的新型6-取代衍生物。各种硫醇与6-甲基-2,3,4-三（羟甲基）吡啶-5-醇（6-羟甲基吡啶恶烷）的单，双和三（氯勒林）衍生物反应生成吡sulfur醇的含硫衍生物。
• Design, synthesis, antibacterial activity and toxicity of novel quaternary ammonium compounds based on pyridoxine and fatty acids
  作者：Sergey V. Sapozhnikov、Alina E. Sabirova、Nikita V. Shtyrlin、Anastasia Y. Druk、Mariya N. Agafonova、Milana N. Chirkova、Renata R. Kazakova、Denis Y. Grishaev、Tatyana V. Nikishova、Elena S. Krylova、Elena V. Nikitina、Airat R. Kayumov、Yurii G. Shtyrlin

  DOI：10.1016/j.ejmech.2020.113100

  日期：2021.2

  membrane suggesting that the membrane is an apparent molecular target of compounds. 6i and 12a were non mutagenic neither in SOS-chromotest nor in Ames test and non-toxic in vivo at acute oral (LD50 > 2000 mg/kg) and cutaneous administration (LD50 >2500 mg/kg) on mice. Taken together, our data allow suggesting the described active compounds as promising starting point for the new antibacterial agents development

  设计了一系列基于季铵吡ido醇衍生物的43种新颖的“软抗菌剂”，其中包括吡soft醇的六元缩醛和缩酮，它们通过可裂解的连接基部分（酰胺，酯）与脂肪羧酸的片段结合。九种化合物对革兰氏阳性和革兰氏阴性细菌菌株具有体外有望的抗菌活性，其MIC值可与参考防腐剂miramistin，苯扎氯铵和氯己定相比。在各种临床分离株上，先导化合物6i和12a表现出与苯扎氯铵相当的抗菌活性，但比miramistin高。此外，6i和12a能够杀死嵌入单物种和双物种生物膜基质中的细菌。用6i和12a处理细菌细胞会导致膜快速去极化，表明该膜是化合物的明显分子靶标。6i和12a在SOS-chromotest和Ames试验中均无致突变性，并且在小鼠急性口服（LD 50 > 2000 mg / kg）和经皮给药（LD 50 > 2500 mg / kg）时体内无毒。综上所述，我们的数据可以表明所描述的活性化合物是新抗菌剂开发的有希望的起点。
• Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine
  作者：Mikhail V. Pugachev、Nikita V. Shtyrlin、Lubov P. Sysoeva、Elena V. Nikitina、Timur I. Abdullin、Alfiya G. Iksanova、Alina A. Ilaeva、Rashid Z. Musin、Eugeny A. Berdnikov、Yurii G. Shtyrlin

  DOI：10.1016/j.bmc.2013.04.051

  日期：2013.7

  phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties

  在吡x嗪衍生物的基础上合成了13种phospho盐，并在体外测试了它们对临床相关菌株的抗菌活性。所有化合物对革兰氏阴性菌几乎没有活性，对革兰氏阳性菌表现出结构依赖性活性。已证明了缩酮保护基在phospho盐中的抗菌特性至关重要。在合成的化合物中，发现5,6-双[三苯基膦基（甲基）]-2,2,8-三甲基-4 H- [1,3]二氧杂[4,5- c ]吡啶二氯化物（化合物20）是对金黄色葡萄球菌和表皮葡萄球菌最有效菌株（MIC 5μg/ ml）。该化合物的抗菌活性机制可能涉及细胞渗透以及与基因组和质粒DNA的相互作用。
• Targeting pathogenic fungi, bacteria and fungal-bacterial biofilms by newly synthesized quaternary ammonium derivative of pyridoxine and terbinafine with dual action profile
  作者：Marsel R. Garipov、Alina E. Sabirova、Roman S. Pavelyev、Nikita V. Shtyrlin、Svetlana A. Lisovskaya、Oksana V. Bondar、Aleksandr V. Laikov、Julia G. Romanova、Mikhail I. Bogachev、Airat R. Kayumov、Yurii G. Shtyrlin

  DOI：10.1016/j.bioorg.2020.104306

  日期：2020.11

  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.