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新型手性二螺环[吲哚啉-3,2'-吡咯烷]-哌啶酮类化合物作为有前景的 COVID-19 候选药物的设计：不对称合成、晶体结构及研究。

Design of Novel Enantiopure Dispirooxindolopyrrolidine-Piperidones as Promising Candidates toward COVID-19: Asymmetric Synthesis, Crystal Structure and Studies.

机构信息

Laboratory of Heterocyclic Chemistry Natural Product and Reactivity (LR11ES39), Department of Chemistry, Faculty of Science of Monastir, University of Monastir, Monastir 5019, Tunisia.

School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo 11578, Egypt.

出版信息

Molecules. 2022 Jun 20;27(12):3945. doi: 10.3390/molecules27123945.

DOI:10.3390/molecules27123945
PMID:35745069
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9228936/
Abstract

Despite the effectiveness of COVID-19 vaccines, there is still an urgent need for discovering new anti-viral drugs to address the awful spread and transmission of the rapidly modifiable virus. In this study, the ability of a small library of enantiomerically pure spirooxindolopyrrolidine-grafted piperidones to inhibit the main protease of SARS-CoV-2 (M) is evaluated. These spiroheterocycles were synthesized by 1,3-dipolar cycloaddition of various stabilized azomethine ylides with chiral dipolarophiles derived from [-(-)-methylbenzyl]-4-piperidone. The absolute configuration of contiguous carbons was confirmed by a single crystal X-ray diffraction analysis. The binding of these compounds to SARS-CoV-2 M was investigated using molecular docking and molecular dynamics simulation. Three compounds , and exhibited stable binding modes interacting with the key subsites of the substrate-binding pocket of SARS-CoV-2 M. The synthesized compounds represent potential leads for the development of novel inhibitors of SARS-CoV-2 main protease protein for COVID-19 treatment.

摘要

尽管 COVID-19 疫苗具有有效性，但仍迫切需要发现新的抗病毒药物来应对这种快速变异病毒的可怕传播和传播。在这项研究中，评估了一小部分对映体纯螺环氧化吲哚吡咯烷接枝哌啶酮抑制 SARS-CoV-2（M）主要蛋白酶的能力。这些螺杂环通过各种稳定的氮烯叶立德与来源于 [-(-)-甲基苄基]-4-哌啶酮的手性二极体的 1,3-偶极环加成反应合成。通过单晶 X 射线衍射分析确定了相邻碳原子的绝对构型。使用分子对接和分子动力学模拟研究了这些化合物与 SARS-CoV-2 M 的结合。三种化合物 、 和 表现出与 SARS-CoV-2 M 的底物结合口袋的关键亚结合位点相互作用的稳定结合模式。合成的化合物代表了开发新型 SARS-CoV-2 主要蛋白酶蛋白抑制剂用于 COVID-19 治疗的潜在先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/0451da7dba3d/molecules-27-03945-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/521f22f0e020/molecules-27-03945-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/ef1656721207/molecules-27-03945-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/3013f7e5a14c/molecules-27-03945-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/07eca75a34cf/molecules-27-03945-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/34e687f1941b/molecules-27-03945-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/809226713e2a/molecules-27-03945-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/031bf1936929/molecules-27-03945-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/26c3aa0fc158/molecules-27-03945-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/32385bef3c89/molecules-27-03945-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/eb888113bb02/molecules-27-03945-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/0451da7dba3d/molecules-27-03945-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/521f22f0e020/molecules-27-03945-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/ef1656721207/molecules-27-03945-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/3013f7e5a14c/molecules-27-03945-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/07eca75a34cf/molecules-27-03945-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/34e687f1941b/molecules-27-03945-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/809226713e2a/molecules-27-03945-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/031bf1936929/molecules-27-03945-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/26c3aa0fc158/molecules-27-03945-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/32385bef3c89/molecules-27-03945-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/eb888113bb02/molecules-27-03945-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9dcc/9228936/0451da7dba3d/molecules-27-03945-g008.jpg

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