S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5-thiol derivatives. 1. Synthesis and characterization

Purpose: To synthesize and characterize S-alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4- oxadiazole-5-thiol derivatives. Methods: 2-(1H-indol-3-yl)acetic acid (1) was reacted with absolute ethanol and catalytic amount of sulfuric acid to form ethyl 2-(1H-indol-3-yl)acetate (2) which was transformed to 2-(1H-indol-3- yl)acetohydrazide (3) by refluxing with hydrazine hydrate in methanol. Ring closure reaction of 3 with carbon disulfide and ethanolic potassium hydroxide yielded 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5- thiol (4) which was finally treated with alkyl/aralkyl halides (5a-u) in DMF and NaH to yield Salkylated/ aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiols (6a-u). Structural elucidation was done by IR, 1H-NMR and EI-MS techniques Results: 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol (4) was synthesized as the parent molecule and was characterized by IR and the spectrum showed peaks resonating at (cm-1) 2925 (Ar-H), 2250 (S-H ), 1593 (C=N ) and 1527 (Ar C=C ); 1H-NMR spectrum showed signals at δ 11.00 (s, 1H, NH-1ʹ), 7.49 ( br.d, J = 7.6 Hz, 1H, H-4\'), 7.37 (br.d, J = 8.0 Hz, 1H, H-7\'), 7.34 (br.s, 1H, H-2\'), 7.09 (t, J = 7.6 Hz, 1H, H-5\'), 7.00 (t, J = 7.6 Hz, 1H, H-6\') and 4.20 (s, 2H, CH2-10ʹ). EI-MS presented different fragments peaks at m/z 233 (C11H9N3OS)˙+ [M+2]+, 231 (C11H9N3OS)˙+ [M]+, 158 (C10H8NO)+, 156 (C10H8N2)˙+, 130 (C9H8N)+. The derivatives (6a-6u) were prepared and characterized accordingly. Conclusion: S-alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiols (6a-u) were successfully synthesized.

Oral glutamate intake reduces acute and chronic effects of ethanol in rodents

Purpose: To assess the effects of oral glutamate intake on acute motor effects and chronic intake of ethanol in rodents. Methods: The acute effects of ethanol on motor function were studied in ICR mice by giving 2 or 6 g/kg of ethanol 2 h after distilled water or 2.5 g/kg glutamate per os. Thirty minutes after ethanol treatment, behavioral assays, including rotarod tests and foot print analysis were monitored. In chronic ethanol treatment, male Wistar rats were trained to consume ethanol-sucrose solution during a 2-h period daily, starting with 2 % ethanol/10 % sucrose and gradually increasing to 10 % ethanol/5 % sucrose solution over 56 days. After training session, the drug treatment phase was done for 10 days. The animals were force-fed 50 mg/kg/day topiramate or 2.5 g/kg/day glutamate 2 h before ethanol treatment sessions. Each day, ethanol intake, water intake, food intake and body weight were recorded. Results: Mice that received 2 or 6 g/kg of ethanol orally, showed a significant reduction in time on the rod in the rotarod test and a significant increase in both forelimb and hindlimb stride lengths when compared to control. Oral treatment with 2.5 g/kg of glutamate reversed the acute motor effects of ethanol. In chronic ethanol treatment, the intake of 10 % ethanol/5 % sucrose, accessible for 2 h, was significantly decreased in rats treated with either topiramate or glutamate. Conclusion: These results provide evidence that oral glutamate administration help to reduce the acute motor effects of ethanol in mice and ethanol intake in the chronic ethanol drinking rats.