Abstract
Several oxidative processes are related to a wide range of human chronic and degenerative diseases, like Alzheimer’s disease, which also has been related to cholinergic processes. Therefore, search for new or improved antioxidant molecules with acetylcholinesterase activity is essential to offer alternative chemotherapeutic agents to support current drug therapies. A series of chalcone (2a–2k) and flavone (3a–3k) analogs were synthesized, characterized, and evaluated as acetylcholinesterase (AChE) inhibitors, and antioxidant agents using 1,1-diphenyl-2-picrylhydrazyl (DPPH•), 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS•), and β-carotene/linoleic acid bleaching assay. Compounds more active were 3j and 2k in DPPH with EC50 of 1 × 10−8 and 5.4 × 10−3 μg/mL, respectively; 2g and 3i in ABTS (1.14 × 10−2 and 1.9 × 10−3 μg/mL); 2e, 2f, 3f, 2j, and 3j exceeded the α-tocopherol control in the β-carotene assay (98–99% of antioxidant activity). At acetylcholinesterase inhibition assay, flavones were more active than chalcones; the best results were compounds 2d and 3d (IC50 21.5 and 26.8 µg/mL, respectively), suggesting that the presence of the nitro group enhances the inhibitory activity. The docking of these two structures were made to understand their interactions with the AChE receptor. Although further in vivo testing must be performed, our results represent an important step towards the identification of improved antioxidants and acetylcholinesterase inhibitors.
Highlights
Radical and non-radical species formed by the partial reduction of oxygen are known as reactive oxygen species (ROS) [1]
Claisen–Schmidt reaction with basic conditions is the most widely synthesis reported in the literature, because of the process and efficiency in the product formation [35]
Chalcone 2d and flavone 3d, both with o-OH and m-NO2 substitutions, were the most active compounds with Inhibitory concentration 50 (IC50) values of 21.5 and 26.8 μg/mL, respectively, these results suggest that the presence of the nitro group in both molecules enhances the inhibitory activity; it has been previously reported that the introduction of basic or permanently charged nitrogen atoms and aromatic systems, are common structural characteristics in molecules for their interaction with the binding sites of acetylcholinesterase [57]
Summary
Radical and non-radical species formed by the partial reduction of oxygen are known as reactive oxygen species (ROS) [1]. When ROS overcame the cellular antioxidant defense system, Appl. Sci. 2019, 9, x FOR PEER REVIEW whether an increase in ROSdisturbs levels orcellular a decrease in the cellular antioxidant oxidative oxidativethrough stress occurs [2], which metabolism, damages cellularcapacity, constituents, and stress occurs [2], which disturbs cellular metabolism, damages cellular constituents, and triggers the triggers the activation of specific signaling pathways [3]. The pathogenesis of several chronic and activation of specific
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