PDF(Pubmed)
Abstract：
Introduction: Phosphodiesterase 7 (PDE7) is a high-affinity cyclic AMP (cAMP)-specific PDE that is expressed in immune and proinflammatory cells. In this work, we explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases. Methods: A series of novel substituted 4-hydrazinoquinazoline derivatives and fused triazoloquinazolines were designed, synthesized, and evaluated in vitro for their PDE7A inhibition activities, in comparison with Theophylline, a non-selective PDE inhibitor, and BRL50481, a selective PDE7A inhibitor. This series of novel quinazoline derivatives were synthesized via multi-step reactions. The reaction sequence began with selective monohydrazinolysis of compounds 2a,b to give 3a,b. Schiff bases 4a-h were synthesized by the reaction of the quinazolylhydrazines 3a,b with various substituted aromatic aldehydes. The reaction of 4a-h with bromine in acetic acid, in turn, gave fused triazoloquinazolines 5a-h. These compounds were characterized by satisfied spectrum analyses mainly including 1HNMR, 13CNMR, and MS together with elemental analyses. Results and discussion: The results of in vitro PDE7A inhibition activity clearly indicated that compounds 4b, 4g, 5c, and 5f exhibited good potency. Molecular docking and molecular dynamic simulation studies further supported our findings and provided the basis of interaction in terms of conventional hydrogen bonds and π-π stacking patterns. The present results lay the groundwork for developing lead compounds with improved phosphodiesterase seven inhibitory activities.
摘要：
简介：磷酸二酯酶7（PDE7）是一种高亲和力的环AMP（cAMP）特异性PDE，在免疫和促炎细胞中表达。在这项工作中,我们探索这种酶家族的选择性小分子抑制剂可能提供一种新的方法来缓解与许多炎症性疾病有关的炎症。方法：设计了一系列新型取代的4-肼基喹唑啉衍生物和稠合三唑并喹唑啉，合成，并在体外评估了它们的PDE7A抑制活性，与茶碱相比，一种非选择性PDE抑制剂，和BRL50481，一种选择性PDE7A抑制剂。该系列新型喹唑啉衍生物是通过多步反应合成的。反应顺序从化合物2a的选择性单肼解开始，B给3a,Procedures.席夫碱4a-h是通过喹唑基肼3a的反应合成的，b与各种取代的芳族醛。4a-h与溴在乙酸中的反应，反过来,得到稠合的三唑并喹唑啉5a-h。这些化合物通过满意的光谱分析进行了表征，主要包括1HNMR，13CNMR,和MS以及元素分析。结果与讨论:体外PDE7A抑制活性的结果清楚地表明,化合物4b,4g,5c,和5f表现出良好的效力。分子对接和分子动力学模拟研究进一步支持了我们的发现，并为常规氢键和π-π堆叠模式的相互作用提供了基础。本研究结果为开发具有改善的磷酸二酯酶7抑制活性的先导化合物奠定了基础。
