Discovery of 3-phenyl-1H-5-pyrazolylamides as PLpro inhibitors through virtual screening and structure optimization

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-03 DOI:10.1016/j.bmcl.2025.130293

Chengwei Wu , Mengdie Ou , Bo Qin , Shuo Wang , Peng Li , Sheng Cui , Haihong Huang , Gang Li

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引用次数: 0

Abstract

The papain-like protease (PLpro) of SARS-CoV-2 has been identified as a pivotal enzyme in viral replication, indicating it a promising target for drug discovery. Utilizing a virtual screening strategy, compound 1 with the N-(3-(5-amino-1H-pyrazol-3-yl)phenyl) benzenesulfonamide scaffold was discovered as a hit targeting PLpro. Structural modification from virtually screened hit 1 led to the development of a series of substituted 3-phenyl-1H-5-pyrazolylamide derivatives. Notably, compounds 14h and 14e exhibited improved PLpro inhibitory activity (IC₅₀ = 14.2 μM and 12.0 μM, respectively) and low cytotoxicity. Further biological evaluation revealed that compound 14e with a thiophene aldehyde group displayed potent binding activity (K_D = 1.86 μM). This 3-phenyl-1H-5-pyrazolylamide scaffold offers significant potential for further development as a novel class of PLpro inhibitors.

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通过虚拟筛选和结构优化发现3-苯基- 1h -5吡唑酰胺作为PLpro抑制剂。

SARS-CoV-2的木瓜蛋白酶（PLpro）已被确定为病毒复制的关键酶，这表明它是一个有希望的药物发现靶点。利用虚拟筛选策略，化合物1与N-（3-（5-氨基- 1h -吡唑-3-基）苯基）苯磺酰胺支架被发现为靶向PLpro的靶点。从虚拟筛选hit 1的结构修饰导致了一系列取代的3-苯基- 1h -5吡唑酰胺衍生物的发展。值得注意的是，化合物14 h和14e具有较好的PLpro抑制活性（IC50分别为 = 14.2 μM和12.0 μM）和较低的细胞毒性。进一步的生物学评价表明，含有噻吩醛基团的化合物14e具有较强的结合活性（KD = 1.86 μM）。这种3-苯基- 1h -5-吡唑酰胺支架作为一种新型PLpro抑制剂具有进一步开发的巨大潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.