Synthesis of Novel Benzazole Derivatives and Evaluation of Their Antidepressant-Like Activities with Possible Underlying Mechanisms

Abstract

Novel benzazole derivative compounds 4a⁻4h were obtained by the reaction of corresponding 2-(benzazol-2-ylthio)acetohydrazide and appropriate 4-substituted benzaldehydes. The chemical structures of the synthesized compounds were elucidated by FT-IR, ¹H-NMR, ¹³C-NMR and LCMS spectroscopic methods. Antidepressant-like effects of the compounds were evaluated by tail suspension test (TST) and modified forced swimming tests (MFST). Moreover, locomotor activities of the animals were assessed by an activity cage apparatus. In the series, compounds 4a, 4b, 4e and 4f (at 50 mg/kg) significantly decreased the immobility time of mice in both of the TST and MFST. The same compounds prolonged the swimming time of animals in MFST without any change in the climbing duration. These data indicated that compounds 4a, 4b, 4e and 4f possess significant antidepressant-like activities. Moreover, pre-treatments with p-chloro-phenylalanine methyl ester (an inhibitor of serotonin synthesis), NAN-190 (a 5-HT_1A antagonist), ketanserin (a 5-HT_2A/2C antagonist), and ondansetron (a 5-HT₃ antagonist) reversed the exhibited pharmacological effects. Results of the mechanistic studies suggested the involvement of serotonergic system and contributions of 5-HT_1A, 5-HT_2A/2C and 5-HT₃ receptors to the antidepressant-like effects of compounds 4a, 4b, 4e and 4f. Furthermore, unchanged locomotor activity of mice following the administrations of these four derivatives confirmed that the presented antidepressant-like effects are specific.

Keywords: activity cage test; antidepressant; benzazole; modified forced swimming test; tail suspension test.

Scheme 1

Synthesis of the target compounds 4a–4h.

Figure 1

The effect of 4a–4h (50 mg/kg) and fluoxetine (20 mg/kg) on immobility time of animals in the tail suspension test. ** p < 0.01, *** p < 0.001, compared with control group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 2

The effect of 4a–4h (50 mg/kg) and fluoxetine (20 mg/kg) on immobility time of animals in the modified forced swimming test. * p < 0.05, ** p < 0.01, *** p < 0.001, compared with control group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 3

The effect of 4a–4h (50 mg/kg) and fluoxetine (20 mg/kg) on swimming time of animals in the modified forced swimming test. * p < 0.05, ** p < 0.01, *** p < 0.001, compared with control group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 4

The effect of 4a–4h (50 mg/kg) and fluoxetine (20 mg/kg) on climbing time of animals in the modified forced swimming test. One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 5

The effect of 4a–4h (50 mg/kg) on horizontal locomotor activities of animals in the activity cage test. ** p < 0.01, compared with control group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 6

The effect of 4a–4h (50 mg/kg) on vertical locomotor activities of animals in the activity cage test. * p < 0.05, compared with control group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 7

Effect of PCPA (100 mg/kg) pre-treatments on antidepressant-like activity induced by compounds 4a, 4b, 4e and 4f in the tail suspension test. ** p < 0.01, *** p < 0.001, compared with control group; ^b p < 0.01, compared with compound 4a administrated group; ^& p < 0.05, compared with compound 4b administrated group; ⁺ p < 0.05, compared with compound 4e administrated group; ^éé p < 0.01, compared with compound 4f administrated group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 8

Effect of NAN-190 (0.5 mg/kg) pre-treatments on antidepressant-like activity induced by compounds 4a, 4b, 4e and 4f in the tail suspension test. ** p < 0.01, *** p < 0.001, compared with control group; ^b p < 0.01, compared with compound 4a administrated group; ^&&& p < 0.001, compared with compound 4b administrated group; ⁺⁺⁺ p < 0.001, compared with compound 4e administrated group; ^ééé p < 0.001, compared with compound 4f administrated group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 9

Effect of ketanserin (1 mg/kg) pre-treatments on antidepressant-like activity induced by compounds 4a, 4b, 4e and 4f in the tail suspension test. ** p < 0.01, *** p < 0.001, compared with control group; ^b p < 0.01, compared with compound 4a administrated group; ^&&& p < 0.001, compared with compound 4b administrated group; ⁺⁺⁺ p < 0.001, compared with compound 4e administrated group; ^éé p < 0.01, compared with compound 4f administrated group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.

Figure 10

Effect of ondansetron (0.3 mg/kg) pre-treatments on antidepressant-like activity induced by compounds 4a, 4b, 4e and 4f in the tail suspension test. *** p < 0.001, compared with control group; ^a p < 0.05, compared with compound 4a administrated group; ^& p < 0.05, compared with compound 4b administrated group; ⁺⁺⁺ p < 0.001, compared with compound 4e administrated group; ^ééé p < 0.001, compared with compound 4f administrated group; One way analysis of variance followed by Tukey HSD multiple comparison test, n = 7.