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Novel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-09-30 , DOI: 10.1021/acsmedchemlett.9b00204
Giovanna Poce 1 , Sara Consalvi 1 , Giulia Venditti 1 , Salvatore Alfonso 2 , Nicoletta Desideri 1 , Raquel Fernandez-Menendez 2 , Robert H. Bates 2 , Lluis Ballell 2 , David Barros Aguirre 2 , Joaquin Rullas 2 , Alessandro De Logu 3 , Michelle Gardner 4 , Thomas R. Ioerger 5 , Eric J. Rubin 4 , Mariangela Biava 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-09-30 , DOI: 10.1021/acsmedchemlett.9b00204
Giovanna Poce 1 , Sara Consalvi 1 , Giulia Venditti 1 , Salvatore Alfonso 2 , Nicoletta Desideri 1 , Raquel Fernandez-Menendez 2 , Robert H. Bates 2 , Lluis Ballell 2 , David Barros Aguirre 2 , Joaquin Rullas 2 , Alessandro De Logu 3 , Michelle Gardner 4 , Thomas R. Ioerger 5 , Eric J. Rubin 4 , Mariangela Biava 1
Affiliation
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In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5–49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome sequencing revealed mutations in the mmpL3 gene.
中文翻译：
对结核分枝杆菌有活性的新型含吡唑类化合物
在这项研究中，合成了49种含有吡啶或吡咯型氮的五元杂环化合物，并对结核分枝杆菌进行了测试。其中，仅在1,3,5-三取代的吡唑5 - 49个在低微摩尔范围展出最小抑制浓度值，并且一些也显示出改进的物理化学轮廓无细胞毒性效应。对三种吡唑进行了动物结核病功效模型研究，与未治疗的小鼠相比，化合物6诱导的肺细菌计数具有统计学上的显着差异。此外，为了确定该系列的目标，产生了抗性，并且全基因组测序揭示了该基因的突变。mmpL3基因。
更新日期：2019-09-30
中文翻译：
对结核分枝杆菌有活性的新型含吡唑类化合物
在这项研究中，合成了49种含有吡啶或吡咯型氮的五元杂环化合物，并对结核分枝杆菌进行了测试。其中，仅在1,3,5-三取代的吡唑5 - 49个在低微摩尔范围展出最小抑制浓度值，并且一些也显示出改进的物理化学轮廓无细胞毒性效应。对三种吡唑进行了动物结核病功效模型研究，与未治疗的小鼠相比，化合物6诱导的肺细菌计数具有统计学上的显着差异。此外，为了确定该系列的目标，产生了抗性，并且全基因组测序揭示了该基因的突变。mmpL3基因。
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