Ayoup Mohammed Salah, Ghanem Mariam, Abdel-Hamid Hamida, Abu-Serie Marwa M, Masoud Aliaa, Ghareeb Doaa A, Hawsawi Mohammed B, Sonousi Amr, Kassab Asmaa E
Department of Chemistry, College of Science, King Faisal University, Al-Ahsa, 31982, Saudi Arabia.
Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria, 21321, Egypt.
BMC Chem. 2024 Jul 13;18(1):130. doi: 10.1186/s13065-024-01235-x.
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 IC values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC values in the range of 16.64-70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC = 5.88 µM). Moreover, oxadiazole derivative 2c (IC = 463.85 µM) was more potent antioxidant than quercetin (IC = 491.23 µM). Compounds 3b (IC = 536.83 µM) and 3c (IC = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC = 140.02 µM) and 4c (IC = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC = 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.
合成了一系列基于1,2,4-恶二唑的新型衍生物，并对其抗阿尔茨海默病（AD）潜力进行了评估。结果表明，11种化合物（1b、2a - c、3b、4a - c和5a - c）对乙酰胆碱酯酶（AChE）表现出优异的抑制潜力，IC值范围为0.00098至0.07920 μM。它们的效力比多奈哌齐（IC = 0.12297 μM）高1.55至125.47倍。相比之下，新合成的恶二唑衍生物IC值在16.64 - 70.82 μM范围内，与卡巴拉汀（IC = 5.88 μM）相比，对丁酰胆碱酯酶（BuChE）的选择性较低。此外，恶二唑衍生物2c（IC = 463.85 μM）作为抗氧化剂比槲皮素（IC = 491.23 μM）更有效。化合物3b（IC = 536.83 μM）和3c（IC = 582.44 μM）表现出与槲皮素相当的抗氧化活性。恶二唑衍生物3b（IC = 14,02 μM）和4c（IC = 117.43 μM）显示出显著的单胺氧化酶B（MAO - B）抑制潜力。它们比安坦（IC = 237.59 μM）更有效。化合物1a、1b、3a、3c和4b表现出显著的单胺氧化酶A（MAO - A）抑制潜力，IC值范围为47.25至129.7 μM。它们的效力比亚甲蓝（IC = 143.6 μM）高1.1至3.03倍。大多数合成的恶二唑衍生物对诱导的人红细胞（HRBCs）裂解提供了显著的保护作用，表明合成化合物无毒，因此使其成为安全的候选药物。结果揭示恶二唑衍生物2b、2c、3b、4a、4c和5a为多靶点抗AD药物。合成的恶二唑衍生物与AChE活性位点的显著相互作用可以从计算上解释其高AChE抑制潜力。化合物2b表现出良好的物理化学性质。所有这些数据表明2b可被视为未来开发的有前景的候选药物。
