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.

中文翻译：

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门口的守护者：埃博拉病毒和马尔堡病毒小分子进入抑制剂的优化


埃博拉和马尔堡（EBOV 和 MARV）丝状病毒感染可导致致命的出血热，并在过去 50 年中引起了 30 多次疫情。目前，尚无 FDA 批准的有效治疗丝状病毒疾病的小分子疗法。为了满足这一未满足的医疗需求，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-（吗啉代甲基）苯甲酰胺 （1） 进行了系统的结构优化，该化合物源于我们之前报道的苗头化合物到先导化合物的努力。第二轮构效关系 （SAR） 涉及化合物 1 的几种解构和重构类似物的设计和合成，然后针对假型 EBOV 和 MARV 进行测试。最有希望的先导物的抗病毒活性在感染测定中得到了进一步验证。优化的类似物对不同的埃博拉病毒表现出理想的抗病毒活性，并且脱靶活性降低。此外，它们还具有类似药物的特性，这使它们成为体内疗效研究的理想选择，这是我们正在进行的针对 EBOV 和 MARV 的药物发现活动的一部分。