Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-12-16 DOI:10.1021/acs.jmedchem.4c01646

Malaika D. Argade, Jazmin Galván Achi, Ryan Bott, Kimberly M. Morsheimer, Callum D. Owen, Christian A. Zielinski, Arsen M. Gaisin, Mario Alvarez, Terry W. Moore, Fan Bu, Fang Li, Michael Cameron, Manu Anantpadma, Robert A. Davey, Norton P. Peet, Lijun Rong, Irina N. Gaisina

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Abstract

Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, N-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (1), borne from our previously reported hit-to-lead effort. This secondary round of structure–activity relationship (SAR) involved the design and synthesis of several deconstructed and reconstructed analogs of compound 1, which were then tested against pseudotyped EBOV and MARV. The antiviral activities of the most promising leads were further validated in infectious assays. The optimized analogs exhibited desirable antiviral activity against different ebolaviruses and reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates for in vivo efficacy studies as part of our ongoing drug discovery campaign against EBOV and MARV.

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门口的守护者埃博拉病毒和马尔堡病毒小分子入口抑制剂的优化

埃博拉病毒和马尔堡病毒（EBOV 和 MARV）丝状病毒感染会导致致命的出血热，在过去 50 年中已造成 30 多起疫情爆发。目前，美国食品和药物管理局尚未批准有效治疗丝状病毒疾病的小分子疗法。为了满足这一尚未满足的医疗需求，我们对早期先导化合物 N-(4-(4-甲基哌啶-1-基)-3-(三氟甲基)苯基)-4-(吗啉甲基)苯甲酰胺 (1) 进行了系统的结构优化。结构-活性关系（SAR）的第二轮研究包括设计和合成化合物 1 的几种解构和重构类似物，然后针对假型 EBOV 和 MARV 进行测试。最有希望的先导化合物的抗病毒活性在感染性试验中得到了进一步验证。优化后的类似物对不同的伊波拉病毒具有理想的抗病毒活性，并减少了脱靶活性。此外，它们还具有类似药物的特性，使其成为体内药效研究的理想候选药物，这也是我们正在进行的抗 EBOV 和 MARV 药物研发活动的一部分。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.