PDF(Pubmed)
Abstract：
Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, 10-13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10-13 were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds 10-13. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is E. Biological results revealed that all the screened compounds 10-13 might serve as selective COX-1 inhibitors. They showed IC50 values ranging from 0.71 μM to 4.82 μM against COX-1 and IC50 values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC50 values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC50 value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC50 values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC50 value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.
摘要：
选择性COX-1抑制剂是血小板聚集和凝血反应的优先治疗靶标。在这项研究中,我们研究了四个新合成化合物的选择性COX-1抑制活性，10-13,以及它们抑制血小板聚集对抗ADP和胶原的能力。采用常规方法合成目标化合物10-13,超声处理，和微波辅助方法。利用显微分析和光谱数据来阐明新化合物10-13的结构。此外,进行光谱NMR实验[NOESY]以强调亚胺基团C=N的双键周围的构型。获得的结果表明，任何相邻质子之间都没有观察到相关性，表明在C=N双键处的构型是E。生物学结果表明,所有筛选的化合物10-13都可以用作选择性COX-1抑制剂。它们对COX-1的IC50值在0.71μM至4.82μM的范围内,对COX-2的IC50值在9.26μM至15.24μM的范围内。它们的COX-1选择性指数介于2.87和18.69之间。这些化合物显示出作为有前途的抗血小板聚集剂的前景。他们有效地防止ADP诱导的血小板聚集，IC50值范围为0.11μM至0.37μM，超过标准阿司匹林，IC50值为0.49μM。此外,它们抑制胶原蛋白诱导的血小板聚集，IC50值为0.12μM至1.03μM，与阿司匹林相比，表现出更好的疗效，其IC50值为0.51μM。对COX-1和COX-2活性位点内的所有目标化合物进行了计算机分子建模，以合理化其对COX-1的选择性抑制活性。发现设计的化合物在COX-1活性位点内的结合相互作用不受塞来昔布的存在的影响。使用B3LYP/6-31G（d，进行p）水平以研究所研究化合物的E型相对于Z型的稳定性。在实验观察和量子化学描述符之间观察到很强的相关性。
