Synthesis, crystal structure and biological evaluation of some novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines

Nitrogen-containing heterocycles are of particular interest and significant importance for the discovery of potent bioactive agents in pharmaceutical industry. The present study reports the synthesis of a library of new conjugated heterocycles including 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (4a -g and 5a-e) and 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazines (6a-h), by cyclocondensation reaction of 4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol 3 with various substituted aromatic acids and phenacyl bromides, respectively. The structures of newly synthesized compounds were characterized by elemental analysis, IR, H-1 and C-13 NMR spectroscopy and in case of 4c by X-ray crystallographic analysis. Newly synthesized triazolothiadiazoles and thiadiazines were screened for acetyl- and butyryl-cholinesterases and alkaline phosphatase inhibition. Almost all of the compounds showed good to excellent activities against acetylcholinesterase more than the reference drugs. Compound 5d exhibited IC50 value 0.77 +/- 0.08 mu M against acetylcholinesterase and 4a showed IC50 9.57 +/- 1.42 mu M against butyrylcholinesterase. Among all the tested compounds, 4a also proved as excellent inhibitor of alkaline phosphatase with IC50 0.92 +/- 0.03 mu M. These heteroaromatic hybrid structures were also tested for their anticancer activity against lung carcinoma (H157) and kidney fibroblast (BHK-21) cell lines and leishmanias. Variable cell growth inhibitory activities were obtained and many compounds exhibit potent %inhibition. (C) 2014 Elsevier Masson SAS. All rights reserved.