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

• A series of novel triazolothiadiazoles and thiadiazines were designed and synthesized.
• Newly synthesized derivatives were investigated as potent cholinesterases.
• Synthesized compounds were screened for alkaline phosphatase inhibitors.
• Novel compounds were tested for their cytotoxic effects against kidney fibroblast cells and lungs carcinoma.
• Antileishmanial activity was also tested for the novel compounds.

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, 1H and 13C 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 μM against acetylcholinesterase and 4a showed IC50 9.57 ± 1.42 μM against butyrylcholinesterase. Among all the tested compounds, 4a also proved as excellent inhibitor of alkaline phosphatase with IC50 0.92 ± 0.03 μM. 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.

The present work reports the synthesis of new series of triazolothiadiazoles and thiadiazines. The prepared compounds have been screened for acetyl- and butyryl-cholinesterase and alkaline phosphatase inhibition. Figure optionsDownload as PowerPoint slide