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

Abstract

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.

Keywords

• 2-Azetidinone
• Anti-depressant activity
• Nootropic activity
• Schiff’s bases
• Sonication
• Stirring