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 thearubigins do not protect against acetaminopheninduced hepatotoxicity in mice

Purpose: To investigate the potential protective effect of oral repeated doses of thearubigins against acetaminophen-induced hepatotoxicity in mice. Methods: Mice were randomly divided into six groups (n=8) and administered the following: Control group (saline), acetaminophen group (saline), N-acetylcysteine group (500 mg/kg/day), and thearubigins groups (60, 70, 100 mg/kg/day). The drugs were given orally by gavage for seven days. On day 7, 1 h after the last dose of treatment, the mice (except control group) were given a single dose of acetaminophen (n-acetyl-p-aminophenol, APAP) orally by gavage (350 mg/kg) and then sacrificed 4 h post-APAP intake. Blood was collected for biochemical measurements and their liver were subjected to biochemical and histopathological assessment. Results: The acetaminophen group showed significant increases (p < 0.001) in serum alanine aminotransferase level, hepatic cytochrome P2E1 level, and serum and hepatic malondialdehyde levels. Moreover it showed significant decrease (p < 0.001) in serum and hepatic glutathione levels. Morphologically, the liver sections showed cellular necrosis, vacuolization, and degeneration around the centrilobular veins. Pretreatment with N-acetylcysteine reversed all acetaminophen-induced changes (p < 0.001 for all biomarkers except for hepatic MDA (p = 0.014) while pretreatment with thearubigins failed to reverse any of them. Conclusion: Oral repeated doses of thearubigins failed to protect against acetaminophen-induced hepatotoxicity in mice and didn\'t affect hepatic cytochrome P2E1 level.