Design, synthesis, and biological evaluation of 1,2,4-oxadiazole-based derivatives as multitarget anti-Alzheimer agents†

Abstract

A series of novel 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their potential anti-Alzheimer disease activity. The results revealed that compounds 2b, 2c, 2d, 3a, 4a, 6, 9a, 9b, and 13b showed excellent inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values in the range of 0.0158 to 0.121 μM. They were 1.01 to 7.78 times more potent than donepezil (IC₅₀ = 0.123 μM). The newly synthesized compounds exhibited lower activity towards butyrylcholinesterase (BuChE) when compared to rivastigmine. Compounds 4b and 13b showed the most prominent inhibitory potential against BuChE with IC₅₀ values of 11.50 and 15 μM, respectively. Moreover, 4b, and 9b were found to be more potent antioxidant agents (IC₅₀ values of 59.25, and 56.69 μM, respectively) in comparison with ascorbic acid (IC₅₀ = 74.55 μM). Compounds 2b and 2c exhibited monoamine oxidase-B (MAO-B) inhibitory activity with IC₅₀ values of 74.68 and 225.48 μM, respectively. They were 3.55 and 1.17 times more potent than biperiden (IC₅₀ = 265.85 μM). The prominent interactions of the compounds with the AChE active site can be used to computationally explain the high AChE inhibitory activity. The results unveiled 1,2,4-oxadiazole derivatives 2c and 3a as multitarget anti-AD agents. The predicted ADME properties for compounds 2b and 4a were satisfactory, and 4a had the highest likelihood of crossing the blood–brain barrier (BBB), making it the optimum compound for future optimization.