Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt.
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt.
Eur J Med Chem. 2023 Apr 5;252:115272. doi: 10.1016/j.ejmech.2023.115272. Epub 2023 Mar 13.
Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary antiviral agents are urgently needed to combat SARS-CoV-2. The viral papain-like protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 PLpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone by 1,2,4-oxadiazole core. Inspired by the multitarget antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among the evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 PLpro (IC7.197 μM) and spike protein RBD (IC = 8.673 μM), with acceptable ligand efficiency metrics, practical LogP (3.8) and safety profile on Wi-38 (CC = 51.78 μM) and LT-A549 (CC = 45.77 μM) lung cells. Docking simulations declared the possible structural determinants of activities and enriched the SAR data for further optimization studies.
尽管疫苗显然在缓解 COVID-19 大流行方面发挥了作用，但仍迫切需要有效的抗病毒药物来对抗 SARS-CoV-2。病毒木瓜蛋白酶样蛋白酶（PLpro）是一个很有前途的治疗靶点，它是两种对病毒复制至关重要的必需蛋白酶之一。然而，它会使宿主免疫感应反应失调。在这里，我们报告了将特权 1,2,4-噁二唑支架重新定位为有希望的 SARS-CoV-2 PLpro 抑制剂，该抑制剂具有潜在的病毒进入抑制作用。该设计策略依赖于模拟先导苯甲酰胺 PLpro 抑制剂 GRL0617 的一般结构特征，用 1,2,4-噁二唑核心取代其药效团酰胺骨架的等排体。受多靶点抗病毒药物的启发，对取代模式进行了合理化设计，以调整支架对其他额外病毒靶点的效力，特别是负责病毒入侵的刺突受体结合域（RBD）。所采用的面部综合协议允许轻松获得各种合理取代的衍生物。在所评估的系列中，2-[5-(吡啶-4-基)-1,2,4-噁二唑-3-基]苯胺（5）对 SARS-CoV-2 PLpro（IC7.197 μM）和刺突蛋白 RBD（IC = 8.673 μM）表现出最平衡的双重抑制潜力，具有可接受的配体效率指标、实际 LogP（3.8）和 Wi-38（CC = 51.78 μM）和 LT-A549（CC = 45.77 μM）肺细胞的安全性特征。对接模拟宣布了活性的可能结构决定因素，并丰富了 SAR 数据以进行进一步的优化研究。
