Discovery of p-Trifluoromethylbenzohydrazide Derivatives as Potent Antiviral Agents against Monkeypox Virus.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-07 eCollection Date: 2025-05-08 DOI:10.1021/acsmedchemlett.5c00075

Sara Rossi, Luca Pozzetti, Gabriele Carullo, Maria Dichiara, Stefania Butini, Marco Radi, Anna Ramunno, Chiara Terrosi, Giovanni Barra, Rita Berisio, Sandra Gemma, Maria Grazia Cusi, Giuseppe Campiani

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Abstract

After the global eradication of smallpox has occurred, Monkeypox virus (MPXV) is nowadays the most significant pathogen affecting humans among orthopoxviruses. The recent growing number of cases worldwide is drawing researchers' attention, prompting for the discovery of new antivirals with optimized synthetic protocols and enhanced efficacy. To date tecovirimat, targeting the membrane-anchored phospholipase p37, is the only drug specifically approved for the treatment of MPXV. In an effort to develop inhibitors with more accessible synthetic protocols and broaden the poorly explored structure-activity relationship (SAR) studies, a new library of tecovirimat analogues has been designed and synthesized. The resulting compounds have been tested in phenotypic assays to evaluate their antiviral inhibitory properties. Spirovirimat (7) was identified as a potent lead compound within this series. Further experiments highlighted that 7 completely abolished extracellular virus production, and in silico studies suggested that 7 and tecovirimat target the same protein.

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对三氟甲基苯并肼衍生物作为猴痘病毒有效抗病毒药物的发现。

在全球消灭天花之后，猴痘病毒（MPXV）目前是正痘病毒中影响人类的最重要病原体。最近世界范围内越来越多的病例引起了研究人员的注意，促使他们发现具有优化合成方案和增强功效的新抗病毒药物。迄今为止，针对膜锚定磷脂酶p37的tecovirimat是唯一被批准用于治疗MPXV的药物。为了开发具有更容易获得的合成方案的抑制剂，并扩大尚未充分探索的结构-活性关系（SAR）研究，设计和合成了一个新的tecovirimat类似物库。所得到的化合物已在表型分析中进行了测试，以评估其抗病毒抑制特性。Spirovirimat(7)被确定为该系列中有效的先导化合物。进一步的实验表明，7完全消除了细胞外病毒的产生，并且计算机研究表明7和tecovirimat靶向相同的蛋白质。

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

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.