Synthesis and Evaluation of New 1,3,4-Thiadiazole Derivatives as Antinociceptive Agents

Abstract

In the current work, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their antinociceptive effects on nociceptive pathways of nervous system. The effects of these compounds against mechanical, thermal and chemical stimuli were evaluated by tail-clip, hot-plate and acetic acid-induced writhing tests, respectively. In addition, activity cage was performed to assess the locomotor activity of animals. The obtained data indicated that compounds 3b, 3c, 3d, 3e, 3g and 3h increased the reaction times of mice both in the hot-plate and tail-clip tests, indicating the centrally mediated antinociceptive activity of these compounds. Additionally, the number of writhing behavior was significantly decreased by the administration of compounds 3a, 3c, 3e and 3f, which pointed out the peripherally mediated antinociceptive activity induced by these four compounds. According to the activity cage tests, compounds 3a, 3c and 3f significantly decreased both horizontal and vertical locomotor activity of mice. Antinociceptive behavior of these three compounds may be non-specific and caused by possible sedative effect or motor impairments.

Keywords: activity cage; antinociceptive; hot-plate; tail-clip; thiadiazole; writhing.

Figure 1

The synthetic route for the preparation of compounds 3a–h. Reagents and conditions: (i) NH₂NH₂·H₂O, ethanol, rt, 5 h; (ii) (1) CS₂/KOH, ethanol, reflux, 10 h; (2) HCl, pH 4–5; (iii) ClCH₂COR, K₂CO₃, acetone, rt, 8 h.

Figure 2

Effects of test compounds (100 mg/kg) and morphine (10 mg/kg) on maximum possible effect (MPE %) values of mice in the tail-clip test. Significance against control group * p < 0.05, ** p < 0.01, *** p < 0.001. Values are given as mean ± SEM. One-way ANOVA post-hoc Tukey’s test, n = 7.

Figure 3

Effects of test compounds (100 mg/kg) and morphine (10 mg/kg) on maximum possible effect (MPE %) values of mice in the hot-plate test. Significance against control group * p < 0.05, ** p < 0.01, *** p < 0.001. Values are given as mean ± SEM. One-way ANOVA post-hoc Tukey’s test, n = 7.

Figure 4

Effects of test compounds (100 mg/kg) and morphine (10 mg/kg) on number of writhing behavior of mice in the acetic acid-induced writhing test. Significance against control group * p < 0.05, ** p < 0.01, *** p < 0.001. Values are given as mean ± SEM. One-way ANOVA post-hoc Tukey’s test, n = 7.

Figure 5

Effects of test compounds (100 mg/kg) on number of (a) horizontal and (b) vertical activity of mice in the activity cage test. Significance against control group * p < 0.05, ** p < 0.01. Values are given as mean ± SEM. One-way ANOVA post-hoc Tukey’s test, n = 7.