设计、合成新型吡啶并[2,3-d]嘧啶衍生物作为用于 COVID-19 治疗的 SARS-CoV-2 Mpro 抑制剂

IF 2.6 3区 化学 Q2 CHEMISTRY, ORGANIC
Eman Mansour , Ahmed M. Sayed , Safaa I. Elewa
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引用次数: 0

摘要

利用常规方法和超声辐照合成了一些基于尿嘧啶片段的吡啶[2,3-d]嘧啶(3a, 3b)、4、(5a-d)、(6a, b)、7-13和(15a-c)。杂环支架如吡啶[2,3-d]嘧啶是药物发现的重要结构元素。它们与不同病毒机制途径的相互作用将在未来的研究中被利用来创造基于杂环的抗病毒药物。因此,本研究的目的是证明杂环支架对SARS CoV-2治疗进展和鉴定的预期贡献。通过光谱数据对新合成的化合物进行了表征,并利用分子对接研究筛选了它们与COVID-19主要蛋白酶的结合活性,根据初步筛选和对接研究的结果,合成的化合物3a, 4, 6a, 13, 15b,和15c采用主蛋白酶法对SARS-CoV-2 Mpro进行体外评价,评价结果表明,肼基吡啶嘧啶4 (IC50值为10.69µM)和三唑嘧啶15c (IC50值为8.723µM)对SARS-CoV-2 Mpro的抑制作用最大。此外,本研究还对合成的化合物4和15c的抑制效果进行了评估,它们对SARS CoV-2的复制具有中等抑制作用。通过分子动力学和对接模拟验证了15c的结合机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design, Synthesis of Novel Pyrido[2,3-d] pyrimidine Derivatives as SARS-CoV-2 Mpro Inhibitors for COVID-19 Therapy
Some of the interesting pyrido[2,3-d] pyrimidines (3a, 3b), 4, (5a–d), (6a, b), 7–13, and (15a–c) based on uracil moiety were synthesized efficiently using a conventional method and ultrasonic irradiation. Heterocyclic scaffolds such as pyrido[2,3-d] pyrimidines are vital structural elements in drug discovery. Their interactions with different viral mechanistic pathways will be leveraged in future research to create heterocycle-based antivirals. Therefore, the purpose of this work is to demonstrate the anticipated contribution of heterocyclic scaffolds to the advancement and identification of SARS CoV-2 treatment, The newly synthesized compounds were characterized by spectral data, and screened for their binding activity toward the main protease of COVID-19 utilizing a molecular docking study, according to the outcome of our initial screening and docking study, the produced compounds 3a, 4, 6a, 13, 15b, and 15c achieved an evaluation in vitro using the SARS-CoV-2 Mpro utilizing the main protease assay, the results of the evaluation showed that the hydrazinylpyridopyrimidine 4 (IC50 value: 10.69 µM) and triazolopyrimidin 15c (IC50 value 8.723 µM) had the greatest inhibitory effects on SARS-CoV-2 Mpro. Additionally, this study was conducted to assess the inhibitory efficacy of the synthesized compounds 4 and 15c, which show moderate inhibition for the replication of SARS CoV-2. Additional molecular dynamics and docking simulations were performed to prove the binding mechanism of 15c.
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来源期刊
Polycyclic Aromatic Compounds
Polycyclic Aromatic Compounds 化学-有机化学
CiteScore
3.70
自引率
20.80%
发文量
412
审稿时长
3 months
期刊介绍: The purpose of Polycyclic Aromatic Compounds is to provide an international and interdisciplinary forum for all aspects of research related to polycyclic aromatic compounds (PAC). Topics range from fundamental research in chemistry (including synthetic and theoretical chemistry) and physics (including astrophysics), as well as thermodynamics, spectroscopy, analytical methods, and biology to applied studies in environmental science, biochemistry, toxicology, and industry. Polycyclic Aromatic Compounds has an outstanding Editorial Board and offers a rapid and efficient peer review process, as well as a flexible open access policy.
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