Discovery of Thiophene Derivatives as Potent, Orally Bioavailable, and Blood–Brain Barrier-Permeable Ebola Virus Entry Inhibitors,Journal of Medicinal Chemistry

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Discovery of Thiophene Derivatives as Potent, Orally Bioavailable, and Blood–Brain Barrier-Permeable Ebola Virus Entry Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-09 , DOI: 10.1021/acs.jmedchem.4c01267
Marcos Morales-Tenorio ₁ , Fátima Lasala ₂ , Alfonso Garcia-Rubia ₁ , Elnaz Aledavood ₁ , Michelle Heung ₃ , Catherine Olal ₃ , Beatriz Escudero-Pérez ₃ , Covadonga Alonso ₄ , Ana Martínez _{1,

5} , César Muñoz-Fontela ₃ , Rafael Delgado _{2,

6,

7} , Carmen Gil _{1,

5}

Affiliation

The endemic nature of the Ebola virus disease in Africa underscores the need for prophylactic and therapeutic drugs that are affordable and easy to administer. Through a phenotypic screening employing viral pseudotypes and our in-house chemical library, we identified a promising hit featuring a thiophene scaffold, exhibiting antiviral activity in the micromolar range. Following up on this thiophene hit, a new series of compounds that retain the five-membered heterocyclic scaffold while modifying several substituents was synthesized. Initial screening using a pseudotype viral system and validation assays employing authentic Ebola virus demonstrated the potential of this new chemical class as viral entry inhibitors. Subsequent investigations elucidated the mechanism of action through site-directed mutagenesis. Furthermore, we conducted studies to assess the pharmacokinetic profile of selected compounds to confirm its pharmacological and therapeutic potential.

中文翻译：

发现硫代酚衍生物作为有效的、口服生物可利用的和可渗透血脑屏障的埃博拉病毒进入抑制剂

埃博拉病毒病在非洲的地方性突出表明需要负担得起且易于管理的预防和治疗药物。通过使用病毒假型和我们内部化学库的表型筛选，我们确定了一个有希望的命中物，该支架具有噻吩支架，在微摩尔范围内表现出抗病毒活性。继这一噻吩命中之后，合成了一系列新的化合物，这些化合物保留了五元杂环支架，同时修饰了几种取代基。使用假型病毒系统的初步筛选和采用正宗埃博拉病毒的验证分析证明了这种新化学类别作为病毒进入抑制剂的潜力。随后的研究阐明了通过定点诱变的作用机制。此外，我们进行了研究以评估所选化合物的药代动力学特征，以确认其药理学和治疗潜力。

更新日期：2024-09-09

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