1-butyl-4-(hydroxymethyl)-3-methyl-1H-1,2,3-triazol-3-ium acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-butyl-4-(hydroxymethyl)-3-methyl-1H-1,2,3-triazol-3-ium acetate
• 英文别名: (1-Butyl-3-methyltriazol-1-ium-4-yl)methanol;acetate；(1-butyl-3-methyltriazol-1-ium-4-yl)methanol;acetate
• 化学式: C₂H₃O₂*C₈H₁₆N₃O
• 分子量: 229.279
• InChiKey: KPFNAYXWALYOEB-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -1.24
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  82.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (1-butyl-1H-1,2,3-triazol-4-yl)methanol 以 水 、 乙腈 为溶剂， 反应 24.0h， 生成 1-butyl-4-(hydroxymethyl)-3-methyl-1H-1,2,3-triazol-3-ium acetate
  参考文献：
  名称：

  Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties

  摘要：

  Triazoles are interesting templates for novel chemotherapeutic drugs. We synthesized here 17 1,3,4-substituted-1,2,3-triazoles that differed in their l'-substituent (variable alkyl chain lengths C3-C12), the 3'-substituent (no substituent, -methyl or -propyl) or the salt form obtained. Several of the compounds were cytotoxic (mu M range) for tumor cells (HL-60, Jurkat, MCF-7, HCT-116), and when the effect was compared to non-transformed cells (Vero), selectivity ratios of up to 23-fold were obtained. To estimate the liability of these potential drug candidates for triggering neurotoxicity, we used the LUHMES cell-based NeuriTox assay. This test quantifies damage to the neurites of human neurons. The four most potent tumoricidal compounds were found to be neurotoxic in a concentration range similar to the one showing tumor cell toxicity. As the neurites of the LUHMES neurons were affected at > 4-fold lower concentrations than the overall cell viability, the novel triazoles were classified as specific neurotoxicants. The structure-activity relationship (SAR) for neurotoxicity was sharply defined and correlated with the one for anti-neoplastic activity. Based on this SAR, two non-neurotoxic compounds were predicted, and testing in the NeuriTox assay confirmed this prediction. In summary, the panel of novel triazoles generated and characterized here, allowed to define structural features associated with cytotoxicity and neurotoxicity. Moreover, the study shows that potential neurotoxic side effects may be predicted early in drug development if highly sensitive test methods for neurite integrity are applied.

  DOI：

  10.1016/j.cbi.2018.06.029

文献信息

• Effect of 1,2,3-triazole salts, non-classical bioisosteres of miltefosine, on Leishmania amazonensis
  作者：Pedro H.F. Stroppa、Luciana M.R. Antinarelli、Arturene M.L. Carmo、Jacy Gameiro、Elaine S. Coimbra、Adilson D. da Silva

  DOI：10.1016/j.bmc.2017.03.051

  日期：2017.6

  Here, we report the effect of new non-classical bioisosteres of miltefosine on Leishmania amazonensis. Fifteen compounds were synthesized and the compound dhmtAc, containing an acetate anion, a side chain of 10 carbon atoms linked to N-1 and a methyl group linked to N-3, showed high and selective biological activity against L. amazonensis. On the intracellular amastigotes, stages of the parasite related to human disease, the IC50 values were near or similar to the 1.0 mu M (0.9, 0.8 and 1.0 mu M on L. amazonensis-WT, and two transgenic L. amazonensis expressing GFP and RFP, respectively), being more active than miltefosine. Furthermore, dhmtAc did not show toxic effects on human erythrocytes and macrophages (CC50 = 115.91 mu M) being more destructive to the intracellular parasites (selectivity index > 115). Promastigotes and intramacrophage amastigotes treated with dhmtAc showed low capacity for reversion of the effect of the compound. A study of the mechanism of action of this compound showed some features of metazoan apoptosis, including cell volume decreases, loss of mitochondrial membrane potential, ROS production, an increase in the intracellular lipid bodies, in situ labeling of DNA fragments by TUNEL labeling and phosphatidylserine exposure to the outerleaflet of the plasma membrane. In addition, the plasma membrane disruption, revealed by PI labeling, suggests cell death by necrosis. No increase in autophagic vacuoles formation in treated promastigotes was observed. Taken together, the data indicate that the bioisostere of miltefosine, dhmtAc, has promising antileishmanial activity that is mediated via apoptosis and necrosis. (C) 2017 Elsevier Ltd. All rights reserved.
• Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties
  作者：Elaine Maria de Souza-Fagundes、Johannes Delp、PedroH.D.M. Prazeres、Lucas Bonfim Marques、Arturene Maria Lino Carmo、Pedro Henrique Fazza Stroppa、Nicolas Glanzmann、Jaffar Kisitu、Dàvid Szamosvàri、Thomas Böttcher、Marcel Leist、Adilson David da Silva

  DOI：10.1016/j.cbi.2018.06.029

  日期：2018.8

  Triazoles are interesting templates for novel chemotherapeutic drugs. We synthesized here 17 1,3,4-substituted-1,2,3-triazoles that differed in their l'-substituent (variable alkyl chain lengths C3-C12), the 3'-substituent (no substituent, -methyl or -propyl) or the salt form obtained. Several of the compounds were cytotoxic (mu M range) for tumor cells (HL-60, Jurkat, MCF-7, HCT-116), and when the effect was compared to non-transformed cells (Vero), selectivity ratios of up to 23-fold were obtained. To estimate the liability of these potential drug candidates for triggering neurotoxicity, we used the LUHMES cell-based NeuriTox assay. This test quantifies damage to the neurites of human neurons. The four most potent tumoricidal compounds were found to be neurotoxic in a concentration range similar to the one showing tumor cell toxicity. As the neurites of the LUHMES neurons were affected at > 4-fold lower concentrations than the overall cell viability, the novel triazoles were classified as specific neurotoxicants. The structure-activity relationship (SAR) for neurotoxicity was sharply defined and correlated with the one for anti-neoplastic activity. Based on this SAR, two non-neurotoxic compounds were predicted, and testing in the NeuriTox assay confirmed this prediction. In summary, the panel of novel triazoles generated and characterized here, allowed to define structural features associated with cytotoxicity and neurotoxicity. Moreover, the study shows that potential neurotoxic side effects may be predicted early in drug development if highly sensitive test methods for neurite integrity are applied.