A series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers were prepared and evaluated in vitro for the acetyl- and butyrylcholinesterase (AChE and BChE) inhibitory activities. These bisuracils are shown to be very effective inhibitors of AChE, inhibiting the enzyme at nano- and lower molar concentrations with extremely high selectivity for AChE vs. BChE. Kinetic analysis showed that the lead compound 2h acts as a slow-binding inhibitor of AChE and possess a long drug-target residence time (τ = 1/k_off = 18.6 ± 7.5 min). Moreover, compound 2h ameliorated muscle weakness in myasthenia gravis rat model with a lower effective dose and longer lasting effect than pyridostigmine bromide. Besides, it was shown that compound 2h has an effect of increasing efficiency of antidotal therapy as a pretreatment for poisoning by organophosphates.

制备了一系列新化合物，其中尿嘧啶和 3,6-二甲基尿嘧啶部分与不同的间隔物桥接，并在体外评估了乙酰胆碱酯酶和丁酰胆碱酯酶（AChE 和 BChE）的抑制活性。这些双尿嘧啶被证明是非常有效的 AChE 抑制剂，在纳米级和更低的摩尔浓度下抑制酶，对 AChE相对于BChE具有极高的选择性。动力学分析表明，先导化合物2h作为 AChE 的慢结合抑制剂，具有较长的药物靶点停留时间（τ = 1/k _off  = 18.6 ± 7.5 分钟）。此外，化合物2h改善重症肌无力大鼠模型的肌肉无力，有效剂量低于溴化吡啶斯的明且持续时间更长。此外，显示化合物2h作为有机磷中毒的预处理具有提高解毒治疗效率的作用。