Background: Considering the limitations of current cholinesterase inhibitor drugs for the
treatment of Alzheimer’s disease, there is ongoing research activities to find out alternative drug
candidates. The aryl-spacer-N-benzyl pharmacophore model has been effectively utilized to design
various types of cholinesterase inhibitor molecules, including donepezil. Within this research study,
we have questioned the significance of the benzyl group within this pharmacophore employing the
urolithin derivatives. Urolithins are benzo[c]chromene analogue metabolites of ellagitannins, abundantly
found in pomegranate and berry fruits.
Methods: Employing the previous experience that urolithin-spacer-N-benzyl yielded out potent
cholinesterase inhibitors, we have designed novel benzo[c]chromene derivatives either lacking the
benzyl group or possessing benzyl group in isoquinoline moiety lacking free N-C bond rotation.
Following the synthesis and structure identification studies the compounds were screened for their
potential to inhibit cholinesterase enzymes. Furthermore, the title compounds were also evaluated
for their potential to prevent cholinesterase-accelerated amyloid beta aggregation. In the final, the
most active compound was examined to find out its interactions with the cholinesterase enzyme
employing a molecular docking study.
Results: The title compounds displayed varying cholinesterase inhibitory potential. Some of the
compounds were found more / comparable activity to the activity of the current drugs employed in
clinic. The potential of the title molecules to inhibit amyloid beta aggregation was found poor.
Conclusion: The title compounds displayed varying cholinesterase inhibitory potential, implying
that the benzyl group is not a must in each design. This was also shown with the molecular docking
studies. On the other hand, the beta amyloid aggregation studies have pointed out that cholinesterase
inhibition does not guarantee the prevention of cholinesterase-accelerated amyloid beta aggregation.