Over recent years, many RNA viruses have been “re-discovered”, including life-threatening flaviviruses, such as Dengue, Zika, and several encephalitis viruses. Since no specific inhibitors are currently available to treat these infections, there is a pressing need for new therapeutics. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) represents a validated target being essential for viral replication and it has no human analog. To date, few NS5 RdRp inhibitor chemotypes have been reported and no inhibitors are currently in clinical development. In this context, after an in vitro screening against Dengue 3 NS5 RdRp of our in-house HCV NS5B inhibitors focused library, we found that 2,1-benzothiazine 2,2-dioxides are promising non-nucleoside inhibitors of flaviviral RdRp with compounds 8 and 10 showing IC₅₀ of 0.6 and 0.9 μM, respectively. Preliminary structure-activity relationships indicated a key role for the C-4 benzoyl group and the importance of a properly functionalized C-6 phenoxy moiety to modulate potency. Compound 8 acts as non-competitive inhibitor and its proposed pose in the so-called N pocket of the RdRp thumb domain allowed to explain the key contribution of the benzoyl and the phenoxy moieties for the ligand binding.

近年来，已经“重新发现”了许多RNA病毒，包括威胁生命的黄病毒，例如登革热，寨卡病毒和几种脑炎病毒。由于目前尚无可用于治疗这些感染的特异性抑制剂，因此迫切需要新的疗法。在黄病毒蛋白中，NS5 RNA依赖的RNA聚合酶（RdRp）代表一种经过验证的靶标，对于病毒复制至关重要，并且没有人类类似物。迄今为止，尚未报道过NS5 RdRp抑制剂的化学型，目前尚无抑制剂在临床开发中。在这种情况下，在针对我们内部HCV NS5B抑制剂重点文库的登革热3 NS5 RdRp进行体外筛选后，我们发现2,1-苯并噻嗪2,2-二氧化物是有望与化合物8结合的黄病毒RdRp的非核苷抑制剂图10和10分别显示IC ₅₀为0.6和0.9μM。初步的结构活性关系表明C-4苯甲酰基的关键作用以及适当官能化的C-6苯氧基部分对调节效能的重要性。化合物8充当非竞争性抑制剂，并且其在RdRp拇指结构域的所谓N口袋中的拟议姿势可解释苯甲酰基和苯氧基部分对配体结合的关键作用。