New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer's disease: design, synthesis, and biological evaluation.

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.