通过在卤代查耳酮上组装苄氧基药效团探索一类新型单胺氧化酶 B 抑制剂,Chemical Biology & Drug Design

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通过在卤代查耳酮上组装苄氧基药效团探索一类新型单胺氧化酶 B 抑制剂
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2023-04-03 , DOI: 10.1111/cbdd.14238
Ashutosh Kumar Singh ₁ , Seong‐Min Kim ₂ , Jong Min Oh ₂ , Mohamed A. Abdelgawad _{3,

4} , Mohammed M. Ghoneim ₅ , T. M. Rangarajan ₆ , Sunil Kumar ₁ , Sachithra Thazhathuveedu Sudevan ₁ , Daniela Trisciuzzi ₇ , Orazio Nicolotti ₇ , Hoon Kim ₂ , Bijo Mathew ₁

Affiliation

合成了八种苄氧基衍生的卤代查耳酮衍生物 ( BB1-BB8 )，并测试了它们抑制单胺氧化酶 (MAO) 的能力。所有化合物对 MAO-A 的抑制效率均低于 MAO-B。此外，大多数化合物在 1 μM 时表现出显着的 MAO-B 抑制活性，残留活性低于 50%。化合物BB4抑制MAO-B的IC ₅₀值为0.062 μM ，其次是化合物BB2 (IC ₅₀ = 0.093 μM)。先导分子比参考 MAO-B 抑制剂（Lazabemide IC ₅₀ = 0.11 μM 和 Pargyline Pargyline IC _{50）表现出良好的活性} = 0.14）。在化合物BB2和BB4中观察到 MAO-B 的高选择性指数 (SI) 值（分别为 430.108 和 645.161）。动力学和可逆性实验表明，BB2和BB4是可逆竞争性 MAO-B 抑制剂，K _i值分别为 0.030 ± 0.014 和 0.011 ± 0.005 μM。Swiss 目标预测证实了两种化合物的 MAO-B 目标的高概率。假设的结合模式表明BB2或BB4与MAO-B 的结合腔具有相似的取向。根据建模结果，BB4在动态模拟过程中表现出稳定的确认。从这些结果得出结论，BB2和BB4是有效的选择性可逆MAO-B抑制剂，可被视为治疗帕金森病等相关神经退行性疾病的候选药物。

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Exploration of a new class of monoamine oxidase B inhibitors by assembling benzyloxy pharmacophore on halogenated chalcones

Eight derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less efficiently inhibited by all compounds than MAO-B. Additionally, the majority of the compounds displayed significant MAO-B inhibitory activities at 1 μM with residual activities of less than 50%. With an IC₅₀ value of 0.062 μM, compound BB4 was the most effective in inhibiting MAO-B, followed by compound BB2 (IC₅₀ = 0.093 μM). The lead molecules showed good activity than the reference MAO-B inhibitors (Lazabemide IC₅₀ = 0.11 μM and Pargyline Pargyline IC₅₀ = 0.14). The high selectivity index (SI) values for MAO-B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO-B inhibitors with K_i values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO-B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO-B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO-B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease.

更新日期：2023-04-03

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