The 3-pyridazinylcoumarin scaffold was previously reported as an efficient core for the discovery of reversible and selective inhibitors of MAO-B, a validated drug target for PD therapy which also plays an important role in the AD progress. Looking for its structural optimization, novel compounds of hybrid structure coumarin-pyridazine, differing in polarizability and lipophilicity properties, were synthesized and tested against the two MAO isoforms, MAO-A and MAO-B (compounds 17a-f and 18a-f).

All the designed compounds selectively inhibited the MAO-B isoenzyme, exhibiting many of them IC₅₀ values ranging from sub-micromolar to nanomolar grade and lacking neuronal toxicity. The 7-bromo-3-(6-bromopyridazin-3-yl)coumarin (18c), the most potent compound of these series (IC₅₀ = 60 nM), was subjected to further in vivo studies in a reserpine-induced mouse PD model. The obtained results suggest a promising potential for 18c as antiparkinsonian agent.

Molecular modeling studies also provided valuable information about the enzyme-drug interactions and the potential pharmacokinetic profile of the novel compounds.

先前曾报道3-吡啶并嗪香豆素支架是发现MAO-B可逆和选择性抑制剂的有效核心，MAO-B是经过验证的PD治疗药物靶标，在AD进展中也起着重要作用。为了寻求结构优化，合成了极化率和亲脂性不同的杂合结构香豆素-哒嗪的新型化合物，并针对两种MAO同工型MAO-A和MAO-B（化合物17a-f和18a-f）进行了测试。

所有设计的化合物均选择性抑制MAO-B同工酶，其中许多IC ₅₀值均在亚微摩尔级至纳摩尔级之间，并且缺乏神经元毒性。7-溴-3-（6-溴哒嗪-3-基）香豆素（18c）是这些系列中最有效的化合物（IC ₅₀  = 60 nM），已在利血平诱导的小鼠PD中进行了进一步的体内研究模型。获得的结果表明18c作为抗帕金森病药物的潜力很大。

分子建模研究还提供了有关酶与药物相互作用以及新型化合物潜在药代动力学特征的有价值的信息。