Background: One of the best methods to treat Alzheimer disease (AD) is through the effective
use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the
Objective: The present study aims the investigation of spiro heterocyclic compounds as potential AD
agents supported by their metal chelation capacity, POM analyses and DFT studies, respectively.
Methods: The cholinesterase inhibition and metal chelation ability were performed on ELISA microtiter
assay. Whereas, the B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMOLUMO
energy calculations. The pharmacokinetic properties of the synthesized molecules were studied
through Petra, Osiris and Molinspiration (POM).
Results: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity.
Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition
against both cholinesterases, while compound 4 proved to be the most active molecule with
57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation
capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising
bindings with AChE and BChE’s active site pertained to hydrophobic hydrogen bonds and positive ionizable
interactions. The POM analyses gave the information about the flexibility at the site of coordination
of spiro compounds (1-6).
Conclusion: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them
show considerable potential to inhibit AChE and BChE. Herein, we propose that the spiro molecules
after further derivatization could serve interesting AD inhibitor drugs.