Abstract：
This research work reports the synthesis of new derivatives of the hydrazone Schiff bases (1-17) based on polyhydroquinoline nucleus through multistep reactions. HR-ESIMS,1H- and 13C-NMR spectroscopy were used to structurally infer all of the synthesized compounds and lastly evaluated for prolyl oligopeptidase inhibitory activity. All the prepared products displayed good to excellent inhibitory activity when compared with standard z-prolyl-prolinal. Three derivatives 3, 15 and 14 showed excellent inhibition with IC50 values 3.21 ± 0.15 to 5.67 ± 0.18 µM, while the remaining 12 compounds showed significant activity. Docking studies indicated a good correlation with the biochemical potency of compounds estimated in the in-vitro test and showed the potency of compounds 3, 15 and 14. The MD simulation results confirmed the stability of the most potent inhibitors 3, 15 and 14 at 250 ns using the parameters RMSD, RMSF, Rg and number of hydrogen bonds. The RMSD values indicate the stability of the protein backbone in complex with the inhibitors over the simulation time. The RMSF values of the binding site residues indicate that the potent inhibitors contributed to stabilizing these regions of the protein, through formed stable interactions with the protein. The Rg. analysis assesses the overall size and compactness of the complexes. The maintenance of stable hydrogen bonds suggests the existence of favorable binding interactions. SASA analysis suggests that they maintained stable conformations without large-scale exposure to the solvent. These results indicate that the ligand-protein interactions are stable and could be exploited to design new drugs for disease treatment.Communicated by Ramaswamy H. Sarma.
摘要：
这项研究工作报道了通过多步反应合成基于多氢喹啉核的腙席夫碱（1-17）的新衍生物。HR-ESIMS,使用1H-和13C-NMR光谱从结构上推断所有合成的化合物，最后评估了脯氨酸寡肽酶的抑制活性。当与标准z-prolyl-prolinal相比时,所有制备的产品都显示出良好至优异的抑制活性。三种衍生物3、15和14显示出优异的抑制作用，IC50值为3.21±0.15至5.67±0.18µM，而其余12种化合物显示出显著的活性。对接研究表明与体外试验中估计的化合物的生物化学效力具有良好的相关性,并显示化合物3、15和14的效力。MD模拟结果证实了最有效的抑制剂3、15和14在250ns时使用参数RMSD，RMSF,Rg和氢键数。RMSD值表明在模拟时间内与抑制剂复合的蛋白质骨架的稳定性。结合位点残基的RMSF值表明有效的抑制剂有助于稳定蛋白质的这些区域。通过与蛋白质形成稳定的相互作用。Rg。分析评估复合物的总体大小和紧密度。维持稳定的氢键表明存在有利的结合相互作用。SASA分析表明,它们在没有大规模暴露于溶剂的情况下保持稳定的构象。这些结果表明配体-蛋白质相互作用是稳定的，可用于设计用于疾病治疗的新药。由RamaswamyH.Sarma沟通。
