Poly(ADP-ribose)polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of the Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC₅₀ = 12 μM), 4 (IC₅₀ = 5.8 μM), and 10 (IC₅₀ = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and it was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC₅₀ = 0.082 μM) as the most potent inhibitor of PARP1 from the series.

聚（ADP-核糖）聚合酶 1 (PARP1) 是一种广泛探索的抗癌药物靶点，在单链 DNA 断裂修复过程中发挥着重要作用。使用 PARP1-苯并咪唑-4-甲酰胺晶体结构和药效团模型对 Maybridge 小分子文库进行高通量虚拟筛选 (HTVS)，鉴定出 11 种化合物。使用重组 PARP1 酶测定法评估这些化合物，从而获得三种 PARP1 抑制剂：3 (IC ₅₀ = 12 μM)、4 (IC ₅₀ = 5.8 μM) 和10 (IC ₅₀ = 0.88 μM)。化合物4(2,3-dihydro-1,4-benzodioxine-5-carboxamide) 被选为先导化合物，并对其进行了进一步的化学修饰，包括类似物合成和支架跳跃。这些努力导致了 ( Z )-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2 H - benzo[ b ][1,4]oxazine-8-carboxamide ( 49 , IC ₅₀ = 0.082 μM）作为该系列中最有效的 PARP1 抑制剂。