Synthesis, computational docking and molecular dynamics studies of a new class of spiroquinoxalinopyrrolidine embedded chromanone hybrids as potent anti-cholinesterase agents.

Novel structurally intriguing heterocycles embedded with spiropyrrolidine, quinoxaline and chromanone units were synthesized in good yields using a [Bmim]Br accelerated multicomponent reaction strategy. The key step of the reaction is 1,3-dipolar cycloaddition involving highly functionalized dipolarophile, viz. 3-benzylidenechroman-4-one, to afford spiroquinoxalinopyrrolidine embedded chromanone hybrid heterocycles. The formation of spiro products occurs via two C-C, two N-C and one C-N bonds possessing four adjoining stereogenic centers, two of which are spiro carbons. The newly synthesized spiro compounds showed potent acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, compounds with fluorine displayed the highest AChE (3.20 ± 0.16 μM) and BChE (18.14 ± 0.06 μM) inhibitory activities. Further, docking studies, followed by all-atom molecular dynamics, showed results that are consistent with in vitro experimental findings. Although docking scores for the synthesized derivatives were higher than those of the standard drug, MD MMPBSA results showed better binding of synthesized derivatives (-93.5 ± 11.9 kcal mol -1 ) compared to the standard drug galantamine (-66.2 ± 12.3 kcal mol -1 ) for AChE but exhibited similar values (-98.1 ± 11.2 and -97.9 ± 11.5 kcal mol -1 ) for BChE. These differences observed in drug binding with AChE/BChE are consistent with RMSD, RMSF, LIG plots, and FEL structural analysis. Taken together, these derivatives could be potential candidates as inhibitors of AChE and BChE.