Synthesis, neurotropic activity and docking studies of 1,2,4-triazole-linked hybrids based on 2,7-naphthyridine and bispidine rings

A series of new 1,2,4-triazole-linked hybrids were synthesized by multistep reactions. Thus, 1-amino-3-chloro-2,7-naphthyridines were subjected to alkylation and then hydrazinolysis. The obtained carbohydrazides were converted into thioureido derivatives, which in turn were cyclized to the corresponding 5-thioxo-1,2,4-triazoles. Bispidine derivatives (3,7-diazabicyclo[3.3.1]non-3-yl(oxo)acetates) were synthesized starting from the 1,5-dialkyl-9-oxo-3,7-diazabicyclo[3.3.1]nonanes. These compounds were reacted with dimethyl oxalate and the obtained monoesters were acylated. After, the reaction of 5-thioxo-1,2,4-triazoles with 7-(chloroacetyl)-1,5-dialkyl-9-oxo-3,7-diazabicyclo[3.3.1]non-3-yl-(oxo)acetates led to the formation of aimed triazole-linked hybrids. The evaluation of neurotropic activity showed that the studied hybrid compounds exhibit pronounced anticonvulsant, anxiolytic and antidepressant properties. Some correlations between the structure and biological activity were revealed. The most active compounds in all biological tests were compounds 9c and 9k, which contain azepane fragment in their structures. Docking study is in agreement with experimental results.