[3+2] Cycloaddition Synthesis of New Piperazine-Linked Bis(chromene) Hybrids Possessing Pyrazole Units as Potential Acetylcholinesterase Inhibitors

Two series of piperazine-linked bis(chromene) hybrids that are attached to pyrazole units were synthesized in the current study. Both series are attached to an acyl unit at pyrazole-C3, with one series attached to an acetyl unit and the other to an ethoxycarbonyl unit. A [3+2] cycloaddition protocol was conducted to produce the target hybrids with good yields by reacting the appropriate hydrazonoyl chlorides with chromene-based bis(enaminone) in dioxane containing triethylamine at reflux for 4 h. New hybrids were tested for acetylcholinesterase inhibitory activity at concentrations of 15 and 25 mu M, as well as their ability to quench 2,2-diphenylpicrylhydrazyl (DPPH) free radicals at a concentration of 25 mu g/mL. In general, the inhibitory activity is related to the electronic properties of the para-substituent that is attached to the arene unit at pyrazole-N1. Furthermore, the acyl unit attached to pyrazole-C3 has a significant effect on the new hybrids ' inhibitory activity. At the previous concentrations, the (3-acetylpyrazole)-linked hybrid attached to p-NO2 units demonstrated the best acetylcholinesterase inhibitory activity, with inhibition percentages of 79.7 and 90.2. Furthermore, the previous hybrid demonstrated the most effective DPPH inhibitory activity, with an inhibition percentage of 87.5.

Automated summary

In this study, two series of piperazine-linked bis(chromene) hybrids were synthesized and tested for their acetylcholinesterase inhibitory activity and ability to quench DPPH free radicals. The inhibitory activity was found to be related to the electronic properties of the para-substituent attached to the arene unit at pyrazole-N1. The acyl unit attached to pyrazole-C3 also had a significant effect on the inhibitory activity of the hybrids. The (3-acetylpyrazole)-linked hybrid attached to p-NO2 units demonstrated the best inhibitory activity and effective DPPH quenching ability.