Synthesis and biological evaluation of Schiff's bases and 2-azetidinones of isonocotinyl hydrazone as potential antidepressant and nootropic agents

The synthesis and pharmacological activity of N′-[(1Z)-(substituted aromatic) methylidene] pyridine-4-carbohydrazides (3a-k) and N-[3-chloro-2-(substituted aromatic)-4-oxoazetidin-1-yl]pyridine-4-carboxamides (5a-k) are described. Synthesis of 2-azetidinones was performed by novel methods of stirring and sonication involving the cyclocondensation of the appropriate Schiff's bases (3a-k) with chloroacetyl chloride, followed by the addition of triethyl amine in the presence of molecular sieves. The compounds were investigated for their antidepressant activity, compounds N′-[(1Z)-(2,5-dimethoxyphenyl)methylidene]pyridine-4-carbohydrazide (3k) and N-[3-chloro-2-(2,5-dimethoxyphenyl)-4-oxoazetidin-1-yl]pyridine-4-carboxamide (5k) with 2,5-dimethoxy substitution on the aryl ring exhibited the highest antidepressant activity. In the elevated plus maze test and passive avoidance test in mice for the evaluation of nootropic activity N′-[(1Z)-(4-nitrophenyl)methylidene]pyridine-4-carbohydrazide (3d) and N-[3-chloro-2-(4-nitrophenyl)-4-oxoazetidin-1-yl]pyridine-4-carboxamide (5d) with para nitro substitution on the aryl ring exhibited the highest activity. All synthesised Schiff's bases and azetidinone analogues exhibited antidepressant and nootropic activities in a dose dependant manner. The results confirmed the fact that the 2-azetidinone skeleton has potential as a CNS active agent and can be explored for the development of more potent and safe CNS active agents for therapeutic use.