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Abstract A series of 8‐(piperazin‐1‐yl) imidazo 1,2 ‐a pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) and antioxidants for the treatment of Alzheimer's disease (AD). Moreover, the biological evaluation results demonstrated that these synthesized compounds exhibited moderate inhibitory activities toward acetylcholinesterase (AChE) and radical scavenging activities. Among them, the compound with the strongest inhibitory activity against AChE had an IC 50 value of 0.55 μM, which was higher than that of galantamine as the reference compound (IC 50 value=5.01 μM). The compound with the strongest antioxidant activity had an IC 50 value of 57.94 μM, which was lower than that of the ascorbic acid (IC 50 value=25.70 μM) as the control drug. Furthermore, the results of molecular docking studies indicated that the compound could simultaneously bind to both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE, which was consistent with the mixed inhibition pattern shown by enzyme kinetic studies. The interaction's stability was also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound in the cavity of the AChE. In addition, the molecular properties of all compounds were predicted online through the SwissADME, and most compounds matched the properties of most orally administered drugs. Based on the biological activity and molecular properties, 8‐(piperazin‐1‐yl) imidazo1,2‐ a pyrazine derivatives as AChEI were valuable for further development.
Wei et al. (Thu,) studied this question.