[3 + 2] Cycloaddition synthesis of new (nicotinonitrile-chromene) hybrids linked to pyrazole units as potential acetylcholinesterase inhibitors

Abstract

Two series of nicotinonitrile-linked chromenes attached to pyrazole units were synthesized in the current study. A [3 + 2] cycloaddition protocol was used to produce the target hybrids in high yields by reacting the respective nitrilimines, which were generated in situ by the action of triethylamine on hydrazonoyl chlorides, with chromene-based enaminone. Generally, the acetylcholinesterase and DPPH free radical inhibitory activity are related to the electronic properties of the para-substituent that is attached to the arene unit at pyrazole-C1. Furthermore, 3-acylpyrazole unit has a significant effect on the new hybrids' efficacy. At 25 and 50 µM concentrations, the 3-acetylpyrazole attached to p-OMe unit demonstrated the best acetylcholinesterase inhibitory activity, with inhibition percentages of 75.8 and 88.3, respectively. Furthermore, the previous hybrid demonstrated the most effective antioxidant activity, with an inhibition percentage of 82.6 at a tested concentration of 25 µg/mL. According to SwissADME, the majority of the pyrazoles tested are drug-like.

Graphical Abstract

Keywords:

• Acetylcholinesterase inhibitors
• [3 + 2] cycloaddition reactions
• DPPH antioxidant activity
• nicotinonitrile-chromene hybrids
• pyrazoles