Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy.
Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy.
Eur J Med Chem. 2023 Jul 5;255:115352. doi: 10.1016/j.ejmech.2023.115352. Epub 2023 Apr 8.
Following a hybridization strategy, a series of 5-substituted-1H-indazoles were designed and evaluated in vitro as inhibitors of human monoamine oxidase (hMAO) A and B. Among structural modifications, the bioisostere-based introduction of 1,2,4-oxadiazole ring returned the most potent and selective human MAO B inhibitor (compound 20, IC = 52 nM, SI > 192). The most promising inhibitors were studied in cell-based neuroprotection models of SH-SY5Y and astrocytes line against HO. Moreover, preliminary drug-like features (aqueous solubility at pH 7.4; hydrolytic stability at acidic and neutral pH) were assessed for selected 1,2,4-oxadiazoles and compared to amide analogues through RP-HPLC methods. Molecular docking simulations highlighted the crucial role of molecular flexibility in providing a better shape complementarity for compound 20 within MAO B enzymatic cleft than rigid analogue 18. Enzymatic kinetics analysis along with thermal stability curves (T shift = +2.9 °C) provided clues of a tight-binding mechanism for hMAO B inhibition by 20.
采用杂交策略，设计并体外评估了一系列 5-取代-1H-吲唑类化合物作为人单胺氧化酶（hMAO）A 和 B 的抑制剂。在结构修饰中，基于生物等排体的 1,2,4-噁二唑环的引入使化合物 20 成为最有效和选择性的人 MAO B 抑制剂（IC = 52 nM，SI > 192）。对最有前途的抑制剂进行了基于细胞的 SH-SY5Y 和星形胶质细胞系针对 HO 的神经保护模型研究。此外，通过反相高效液相色谱（RP-HPLC）方法评估了所选 1,2,4-噁二唑类化合物的初步类药性特征（在 pH 7.4 时的水溶解度；在酸性和中性 pH 时的水解稳定性），并与酰胺类似物进行了比较。分子对接模拟突出了分子柔性在提供与 MAO B 酶裂口中化合物 20 更好的形状互补性方面的关键作用，优于刚性类似物 18。酶动力学分析以及热稳定性曲线（T shift = +2.9°C）为 20 对 hMAO B 抑制的紧密结合机制提供了线索。
