Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone (E)‐3‐(4‐(dimethylamino)phenyl)‐1‐(2‐hydroxyphenyl)prop‐2‐en‐1‐one: An in vivo and in silico approach

Abstract

BackgroundAnxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3‐diphenyl‐2‐proper‐1‐ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABAA receptors and serotonergic system.ObjectivesThis study evaluated the anxiolytic potential of chalcone (E)‐3‐(4‐(dimethylamino)phenyl)‐1‐(2‐hydroxyphenyl)prop‐2‐en‐1‐one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa).MethodsEach animal (n = 6/group) was treated intraperitoneally (i.p.; 20 μL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 μL), being submitted to the tests of locomotor activity and 96‐h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5‐HT) was evaluated through the antagonists of the 5‐HTR1, 5‐HTR2A/2C, and 5‐HTR3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration.ResultsAs a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5‐HT2A and 5‐HTR3A/3B receptors. The interaction of C2OHPDA with 5‐HT2AR and 5‐HT3A receptors was confirmed by molecular docking study, the affinity energy observed was −8.7 and −9.1 kcal/mol, respectively.ConclusionThus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.

Flavonoids as anxiolytics in animal tests: Bibliometry and meta-analysis of the effects of flavonoids on anxiety-like behavior in animal tests

“…Apigenin, on the other hand, appears to act on GABA A receptors either as an inverse agonist or as an antagonist at the central BZD binding site (Avallone et al, 2000; Dekermendjian et al, 1999; Zanoli et al, 2000), and inspection of the forest plot in Figure 4A suggest that this molecule does not have a clear anxiolytic-like effect in animal tests. There is also some evidence for a participation of the central BZD site on the effects of chalcones, at least in zebrafish (Ferreira et al, 2020, 2021; Santos Oliveira et al, 2024). On the other hand, flavones and chalcones also appear to act at other targets, including monoaminergic neurotransmission (Carradori et al, 2016) and redox balance (Hritcu et al, 2017).…”