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Novel Pyruvate Kinase (PK) Inhibitors: New Target to Overcome Bacterial Resistance
ChemistrySelect ( IF 1.9 ) Pub Date : 2020-03-19 , DOI: 10.1002/slct.202000043 Mardia T. El Sayed 1 , Alaadin E. Sarhan 2 , Entsar Ahmed 3 , Reham R. Khattab 4 , Mohamed Elnaggar 5 , Shahenda M. El‐Messery 6 , Moataz A. Shaldam 7 , Ghada S. Hassan 8
ChemistrySelect ( IF 1.9 ) Pub Date : 2020-03-19 , DOI: 10.1002/slct.202000043 Mardia T. El Sayed 1 , Alaadin E. Sarhan 2 , Entsar Ahmed 3 , Reham R. Khattab 4 , Mohamed Elnaggar 5 , Shahenda M. El‐Messery 6 , Moataz A. Shaldam 7 , Ghada S. Hassan 8
Affiliation
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In the present investigation, some novel nitro Mannich bases derived from Michael type addition of activated nitro olefin, β‐nitrostyrene with various amines either primary or secondary including some amino sugars were designed and synthesized. The produced Mannich bases have been full characterized through different spectroscopic techniques. Antimicrobial evaluation has been performed against the Gram positive S. aureus and methicillin‐resistant S. aurues (MRSA) infections. 5 of the synthesized compounds represent the best candidates in the biological screening, they have exhibited good activity with MIC values range from 100 to 250 μg/ml. The active agents have been tested for pyruvate kinase inhibition activity with % of inhibition range from 30 to 79 % with IC50 in a nano molar range. They also exhibited significant Pyruvate kinase inhibition in nanomolar range with IC50 of 1066, 662, 1887, 418 and 1128 ng/ml, respectively (versus 196 ng/ml for AZD7545). Molecular docking calculations for active agents were performed. A complete conformational analysis molecular modeling utilizing Gaussian 09 program (HF/DFT) was used to verify the mode of bonding through the optimized geometries as well as essential quantum parameters were calculated using frontier energies (EHOMO & ELUMO) for the active candidates indicating the overall stability of the structure.
中文翻译：
新型丙酮酸激酶（PK）抑制剂：克服细菌耐药性的新目标
在本研究中，设计并合成了一些新颖的硝基曼尼希碱，这些碱衍生自活化型硝基烯烃，β-硝基苯乙烯与伯胺或仲胺（包括一些氨基糖）的各种胺的迈克尔型加成反应。所生产的曼尼希碱已通过不同的光谱技术进行了全面表征。抗微生物评价兑革兰氏阳性被执行的金黄色葡萄球菌和耐甲氧西林S. aurues（MRSA）感染。5种合成化合物代表了生物筛选的最佳候选物，它们具有良好的活性，MIC值为100至250μg/ ml。测试了活性剂的丙酮酸激酶抑制活性，IC 50抑制百分比范围为30％至79％在纳米摩尔范围内。它们还显示出在纳摩尔范围内的丙酮酸激酶抑制作用，IC 50分别为1066、662、1887、418和1128 ng / ml（而AZD7545为196 ng / ml ）。进行了活性剂的分子对接计算。使用高斯09程序（HF / DFT）的完整构象分析分子建模来验证通过优化的几何构图的键合模式，并使用前沿能量（EHOMO＆ELUMO）计算了活性候选物的基本量子参数，从而表明了整体结构的稳定性。
更新日期：2020-03-20
中文翻译：
新型丙酮酸激酶（PK）抑制剂：克服细菌耐药性的新目标
在本研究中，设计并合成了一些新颖的硝基曼尼希碱，这些碱衍生自活化型硝基烯烃，β-硝基苯乙烯与伯胺或仲胺（包括一些氨基糖）的各种胺的迈克尔型加成反应。所生产的曼尼希碱已通过不同的光谱技术进行了全面表征。抗微生物评价兑革兰氏阳性被执行的金黄色葡萄球菌和耐甲氧西林S. aurues（MRSA）感染。5种合成化合物代表了生物筛选的最佳候选物，它们具有良好的活性，MIC值为100至250μg/ ml。测试了活性剂的丙酮酸激酶抑制活性，IC 50抑制百分比范围为30％至79％在纳米摩尔范围内。它们还显示出在纳摩尔范围内的丙酮酸激酶抑制作用，IC 50分别为1066、662、1887、418和1128 ng / ml（而AZD7545为196 ng / ml ）。进行了活性剂的分子对接计算。使用高斯09程序（HF / DFT）的完整构象分析分子建模来验证通过优化的几何构图的键合模式，并使用前沿能量（EHOMO＆ELUMO）计算了活性候选物的基本量子参数，从而表明了整体结构的稳定性。
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