Synthesis and Reactions of New Fused Heterocycles Derived from 5-Substituted-4-Amino-3-Mercapto-(4H)-1,2,4-Triazole with Biological Interest

Abstract

The reaction of thiocarbohydrazide with carboxylic acids at the melting temperature allows an improved preparation of 5-substituted-4-amino-3-mercapto 1,2,4-triazoles 1 _{a − g} . Compound 1 _a reacted with 2-bromopropionic acid to give acid derivative 2 . The latter was reacted with a mixture of acetic anhydride and triethylamine to afford the mesoionic compound 3 . Heating of compound 3 in ethanol gave the ester derivative 4 , which on alkaline hydrolysis in methanol gave ketone derivative 5 . Substituted 1,2,4-triazolo [3,4-b]-6H-1,3,4-thiadiazine 6 _h,i and 7 were synthesized by reaction of 1 _a with acetylacetone, ethyl acetoacetate and chloroacetamide. Heterocyclic systems 8 and 9 were prepared through the reaction of 1 _a with 2,3-dichloro-1,4-naphthoquinone and 2,3-dichloroquinoxaline. In addition, thenoyl isothiocyanate, thenoyl chloride, 2-thiophenecarbaldehyde, and p-chlorophenyl isocyanate reacted with compound 1 _a to afford 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole ring system 10 , 11 , and urea derivative 12 . 1,2,4-Triazolo[3,4-b]-5H-pyrazole derivatives 14 _j,k were prepared through the reaction of compound 1 _a with 3-chloro-2,4-pentandione and ethyl-2-chloroacetoacetate. Compound 14 _j was treated with hydrazine to afford products 15 , 16 , and 17 depending on the type of hydrazine derivative and reaction conditions. Compound 19 was synthesized by refluxing of compound 14 _j with hydroxylamine hydrochloride to afford the corresponding oxime derivative 18 followed by treatment with thenoyl chloride.

Keywords:

• Pyrazoles
• 5-substituted-4-amino-3-mercapto-(4H)-1,2,4-triazole
• 1,3,4-thiadiazines
• 1,3,4-thiadiazoles

Notes

∗ 1 _g : Br: Calcd 35.86; Found: 36.01.

^a Liver carcinoma cell line.

^b Concentration of compound that causes 50% inhibition of cell growth.

^c Positive control.