Design, Synthesis, and In Vivo and In Silico Evaluation of Coumarin Derivatives with Potential Antidepressant Effects

Abstract

In this study, a series of coumarin derivatives were designed and synthesized, their structures were characterized using nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) testing methods. In the pharmacological experiment, two behavior-monitoring methods, the forced swim test (FST) and the tail suspension test (TST), were used to determine the antidepressant activity of coumarin derivatives. Compounds that showed potential activity were analyzed for their effects on 5-hydroxytryptamine (5-HT) levels in the brains of mice. Molecular docking experiments to simulate the possible interaction of these compounds with the 5-HT_1A receptor was also be predicted. The results of the pharmacological experiments showed that most coumarin derivatives exhibited significant antidepressant activity. Among these compounds, 7-(2-(4-(4-fluorobenzyl)piperazin-1-yl)-2-oxoethoxy)-2H-chromen-2-one (6i) showed the highest antidepressant activity. The results of the measurement of 5-HT levels in the brains of mice indicate that the antidepressant activity of coumarin derivatives may be mediated by elevated 5-HT levels. The results of molecular docking demonstrated that compound 6i had a significant interaction with amino acids around the active site of the 5-HT_1A receptor in the homology model. The physicochemical and pharmacokinetic properties of the target compounds were also predicted using Discovery Studio (DS) 2020 and Chemdraw 14.0.

Keywords: 5-HT; FST; antidepressant; coumarin; molecular docking studies; synthesis.

Figure 1

Design strategy for target compounds 6a–u.

Scheme 1

Synthesis of the target compounds. Reagents and conditions: (i) ClCH₂COCl, K₂CO_3, DCM, rt, 8–24 h; (ii) K₂CO₃/KI, acetone, reflux, 25–30 h; (iii) CF₃COOH, DCM, rt, 1 h, (iv) RBr, K₂CO₃/KI, CH₃CN, reflux, 24 h.

Figure 2

Antidepressant activities of compounds 6i and Fluoxetine in FST at different doses. Compound 6i and Fluoxetine were administered at 40, 20, and 10 mg/kg, respectively. Values represent the mean ± SEM (n = 8). * Significant compared to control (0.01 < p < 0.05). ** Very significant compared to control (p < 0.01).

Figure 3

Antidepressant activities of compounds 6i and Fluoxetine in the TST test. Compounds 6i and Fluoxetine were administered at 40 mg/kg. Values represent the mean ± SEM (n = 8). * Significant compared to control (0.01 < p < 0.05).

Figure 4

Exploratory activity (counts) in the OFT. The behavioral parameters were recorded for 3 min. Locomotion: number of line crossings; rearing: number of times seen standing on hind legs; grooming: number of modifications; 6i (40 mg/kg) was administered 60 min before the test. The values represent the mean ± SEM (n = 8).

Figure 5

Effect of compounds 6i and Fluoxetine on brain 5-HT level in mice. Compounds 6i and Fluoxetine were analyzed by the concentration of 5-HT in the mice brain 1 h after oral administration. Values represent the mean ± SEM (n = 8). * Significant compared to control (0.01 < p < 0.05).

Figure 6

SARs of target compounds 6a–u.

Figure 7

(A) Binding pocket of compound 6i and serotonin to the 5-HT_1A receptor—homology model; (B) compound 6i shows interactions with residues at the 5-HT_1A receptor. (C) Serotonin shows interactions with residues at the 5-HT_1A receptor.

Figure 8

Target compounds 6a–u ADME/T value prediction. The blue dots in the four circular circles indicate that the compound has good pharmacokinetic properties, such as good ABS and favorable BBB permeability.