The effective treatment for dengue virus infection continues to be a challenge. We herein reported our continued SAR exploration on the spiropyrazolopyridone scaffold. Introducing different substituents at the 3́- or 5́-site of the pyrazolopyridone core or moving the benzyl chain to the adjacent nitrogen led to a significant loss of potency on DENV-2. While a narrow range of substitutions were tolerated at the para-position of the phenyl ring, di-substitution on the phenyl ring is beneficial for DENV-2 potency and has variable influences on DENV-3 potency depending on the exact compound. Among these molecules, compounds 22 (JMX0376) with 4-chloro-3-fluorobenzyl and 24 (JMX0395) with 2,4-bis(trifluoromethyl)benzyl showed the most potent and broadest inhibitory activities against DENV-1 to -3 with nanomolar to low micromolar EC50 values.

中文翻译：

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螺吡唑并吡啶酮衍生物作为有效登革热病毒抑制剂的设计、合成和生物学评价。

登革热病毒感染的有效治疗仍然是一个挑战。我们在此报告了我们对螺吡唑并吡啶酮支架的持续 SAR 探索。在吡唑并吡啶酮核心的 3́- 或 5́-位点引入不同的取代基或将苄基链移动到相邻的氮原子会导致对 DENV-2 的效力显着丧失。虽然在苯环的对位可以容忍窄范围的取代，但苯环上的二取代对 DENV-2 效力有益，并且对 DENV-3 效力的影响取决于确切的化合物。在这些分子中，具有 4-氯-3-氟苄基的化合物 22 (JMX0376) 和具有 2,4-双(三氟甲基)苄基的化合物 24 (JMX0395) 对 DENV-1 至 -3 显示出最有效和最广泛的抑制活性，具有纳摩尔至低微摩尔 EC50 值。