Metabolism-directed structure optimization of benzimidazole-based Francisella tularensis enoyl-reductase (FabI) inhibitors.
Metabolism-directed structure optimization of benzimidazole-based Francisella tularensis enoyl-reductase (FabI) inhibitors.
复制标题
代谢指导的结构优化基于苯咪唑的francisella tularensis enoyl-还原酶（FABI）抑制剂。
DOI：
10.3109/00498254.2013.850553
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Jeong H
中科院分区：
文献类型：
--
作者：
Zhang YY;Liu Y;Mehboob S;Song JH;Boci T;Johnson ME;Ghosh AK;Jeong H
FabI是针对土拉弗朗西斯菌的潜在抗生素靶标，土拉弗朗西斯菌已被列为对公共卫生具有高风险的A类生物战剂。我们以前的工作表明，N-苄基苯并咪唑类化合物具有很好的FabI抑制活性，但其可药用性，包括代谢稳定性是未知的。本研究的目的是表征一系列N-苄基苯并咪唑化合物的结构-代谢关系，以指导化学优化以获得更好的代谢稳定性。为此，使用小鼠肝微粒体获得了22种初始先导化合物的代谢稳定性数据。通过对4种模型化合物的代谢物鉴定研究，确定并验证了苯并咪唑核心结构以及苄基环上的代谢热点。有趣的是，所提出的结构-代谢关系并不适用于9个新合成的环戊烷或氧杂环戊烷衍生物的N-苄基苯并咪唑。随后，开发了计算机定量结构-性质关系模型。确定了代表分子极性/极化率、对称性和大小的四个分子描述符，以最好地解释不同化合物代谢稳定性的变异性。基于所选择的分子描述符的多线性和非线性回归模型的开发和验证。N-苄基苯并咪唑类化合物的结构-代谢关系有助于优化N-苄基苯并咪唑类化合物的药代动力学行为。
FabI is a potential antibiotic target against Francisella tularensis, which has been classified as a Category A biowarfare agent of high risk to public health. Our previous work demonstrated that N-benzyl benzimidazole compounds possess promising FabI inhibitory activity, but their druggability properties including metabolic stability are unknown. The objective of this study was to characterize structure-metabolism relationships of a series of N-benzyl benzimidazole compounds to guide chemical optimization for better metabolic stability. To this end, metabolic stability data were obtained for 22 initial lead compounds using mouse hepatic microsomes. Metabolic hotspots on the benzimidazole core structure as well as the benzyl ring were identified and verified by metabolite identification studies of 4 model compounds. Interestingly, the proposed structure-metabolism relationships did not apply to 9 newly synthesized cyclopentane or oxacyclopentane derivatives of N-benzyl benzimidazole. Subsequently, in silico quantitative structure-property relationship models were developed. Four molecular descriptors representing molecular polarity/polarisability, symmetry and size were identified to best explain variability in metabolic stability of different compounds. Multi-linear and nonlinear regression models based on the selected molecular descriptors were developed and validated. The structure-metabolism relationships for N-benzyl benzimidazole compounds should help optimization of N-benzyl benzimidazole compounds for better pharmacokinetic behavior.
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