Annual unpredictable efficacy of vaccines, coupled with emerging drug resistance, underlines the development of new antiviral drugs to treat influenza infections. The N-terminal domain of the PA (PA_N) endonuclease is both highly conserved across influenza strains and serotypes and is indispensable for the viral lifecycle, making it an attractive target for new antiviral therapies. Here, we describe the discovery of a new class of PA_N inhibitors derived from recently identified, highly active hits for PA_N endonuclease inhibition. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a fragment growing strategy, giving rise to a series of 1, 3-cis-2-substituted-1-(3, 4-dihydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid derivatives as potent PA_N inhibitors. This approach ultimately resulted in the development of a new lead compound 13e, which exhibited an EC₅₀ value of 4.50 μM against H1N1 influenza virus in MDCK cells.

疫苗每年不可预测的功效，加上新出现的耐药性，强调了开发新的抗病毒药物来治疗流感感染。PA (PA _N ) 核酸内切酶的 N 末端结构域在流感病毒株和血清型中高度保守，并且对于病毒生命周期是必不可少的，使其成为新抗病毒疗法的有吸引力的靶标。在这里，我们描述了一种新的 PA _N抑制剂的发现，这些抑制剂来源于最近发现的 PA _{N高活性命中}核酸内切酶抑制。通过使用结构导向设计和系统的 SAR 探索，通过片段生长策略对命中进行了详细阐述，产生了一系列 1, 3-cis-2-取代-1-(3, 4-dihydroxybenzyl)-6, 7-二羟基-1, 2, 3, 4-四氢异喹啉-3-羧酸衍生物作为有效的 PA _N抑制剂。这种方法最终导致开发了一种新的先导化合物13e，其在 MDCK 细胞中对 H1N1 流感病毒的 EC ₅₀值为 4.50 μM。