PDF(Pubmed)
Abstract：
A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64-70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives\' significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.
摘要：
合成了一系列新的基于1,2,4-恶二唑的衍生物，并评估了它们的抗AD潜力。结果表明，11个化合物(1b，2a-c,3b,4a-c,和5a-c）对AChE表现出优异的抑制潜力，IC50值范围为0.00098至0.07920µM。它们的效力是多奈哌齐的1.55至125.47倍（IC50=0.12297µM）。相比之下,与卡巴拉汀相比，新合成的IC50值在16.64-70.82µM范围内的恶二唑衍生物对BuChE的选择性较低（IC50=5.88µM）。此外，恶二唑衍生物2c(IC50=463.85µM)比槲皮素(IC50=491.23µM)更有效的抗氧化剂。化合物3b(IC50=536.83μM)和3c(IC50=582.44μM)表现出与槲皮素相当的抗氧化活性。恶二唑衍生物3b（IC50=140.02µM）和4c（IC50=117.43µM）显示出突出的MAO-B抑制潜力。它们比Biperiden更有效(IC50=237.59µM)。化合物1a,1b,3a,3c,和4b表现出显著的MAO-A抑制潜力，IC50值范围为47.25至129.7µM。它们的效力是亚甲蓝的1.1至3.03倍（IC50=143.6µM）。大多数合成的恶二唑衍生物对诱导的HRBC裂解提供了显著的保护作用，揭示合成化合物的无毒效果，从而使它们成为安全的候选药物。结果揭示了恶二唑衍生物2b，2c,3b,4a,4c,和5a作为多靶标抗AD剂。高AChE抑制潜力可以通过计算解释合成的恶二唑衍生物与AChE活性位点的显著相互作用。化合物2b显示出良好的理化性质。所有这些数据表明，2b可以被认为是未来发展的有希望的候选人。
