Synthesis and evaluation of phenylimidazole FabK inhibitors as new Anti-C. Difficile agents.
Synthesis and evaluation of phenylimidazole FabK inhibitors as new Anti-C. Difficile agents.
复制标题
新型Anti-C苯基咪唑FabK抑制剂的合成与评价。
DOI：
10.1016/j.bmc.2023.117330
复制
发表时间：
2023
影响因子：
3.5
通讯作者：
Sun,Dianqing
中科院分区：
文献类型：
--
作者：
Norseeda,Krissada;BinAzizPavel,Fahad;Rutherford,JacobT;Meer,HumnaN;Dureja,Chetna;Hurdle,JulianG;Hevener,KirkE;Sun,Dianqing
先前，1-（（4-（4-溴苯基）- 1h -咪唑-2-基）甲基）-3-（5-（吡啶-2-基硫）噻唑-2-基）尿素对艰难梭菌烯酰酰基载体蛋白（ACP）还原酶II酶（FabK）具有选择性抑制活性。该化合物对cdfabk的抑制作用转化为在低微摩尔范围内具有良好的抗菌活性。在这些研究中，我们试图扩大我们对苯咪唑ecdfabk抑制剂系列的SAR的了解，同时提高化合物的效力。合成并评价了三个主要系列化合物：1)吡啶头部基团修饰（包括取代苯并噻唑部分），2)连接体探索，3)苯基咪唑尾部基团修饰。总体而言，cdfabk抑制得到改善，同时保持全细胞抗菌活性。具体而言，化合物1-（（4-（4-溴苯基）- 1h -咪唑-2-基）甲基）-3-（5-（3-（3-（三氟甲基）吡啶-2-基）硫代）噻唑-2-基）尿素、1-（（4-（4-溴苯基）- 1h -咪唑-2-基）甲基）-3-（6-（三氟甲基）苯并[d]噻唑-2-基）尿素和1-（（4-（4-溴苯基）- 1h -咪唑-2-基）甲基）-3-（6-（4-（4-溴苯基）- 1h -咪唑-2-基）甲基）-（6-（6-氯苯并[d]噻唑-2-基）尿素对cdfabk具有抑制作用（IC50= 0.10 ~ 0.24 μM））。与1-（（4-（4-溴苯基）- 1h -咪唑-2-基）甲基）-3-（5-（吡啶-2-基硫代）噻唑-2-基）尿素相比，抗- c的生化活性提高了5至10倍。艰难度范围为1.56 ~ 6.25 μg/mL。在计算分析的支持下，对扩展后的SAR进行了详细的分析。
Previously, 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(5-(pyridin-2-ylthio)thiazol-2-yl)urea bearing ap-bromine substitution was shown to possess selective inhibitory activity against theClostridioides difficileenoyl-acyl carrier protein (ACP) reductase II enzyme, FabK. Inhibition ofCdFabK by this compound translated to promising antibacterial activity in the low micromolar range. In these studies, we sought to expand our knowledge of the SAR of the phenylimidazoleCdFabK inhibitor series while improving the potency of the compounds. Three main series of compounds were synthesized and evaluated based on: 1) pyridine head group modifications including the replacement with a benzothiazole moiety, 2) linker explorations, and 3) phenylimidazole tail group modifications. Overall, improvement in theCdFabK inhibition was achieved, while maintaining the whole cell antibacterial activity. Specifically, compounds 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(5-((3-(trifluoromethyl)pyridin-2-yl)thio)thiazol-2-yl)urea, 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)urea, and 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(6-chlorobenzo[d]thiazol-2-yl)urea showedCdFabK inhibition (IC50= 0.10 to 0.24 μM), a 5 to 10-fold improvement in biochemical activity relative to 1-((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)-3-(5-(pyridin-2-ylthio)thiazol-2-yl)urea, with anti-C. difficileactivity ranging from 1.56 to 6.25 μg/mL. Detailed analysis of the expanded SAR, supported by computational analysis, is presented.