Design, synthesis, biological evaluation and molecular docking of cyclic biguanidine compounds as cholinesterase inhibitors.

A series of cyclic biguanidine derivatives (E01-E16) was designed, synthesized, characterized by FTIR, NMR, elemental analysis and evaluated as cholinesterase [acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)] inhibitory effects for the treatment of Alzheimer's disease (AD). The cyclic biguanidine derivatives (E01-E16) were obtained as hydrochloride salt from one-pot reaction of 2-cyanoguanidine, p-substitute aniline derivatives and cyclohexanone/4-ethylcyclohexanone in the acidic medium. The crystal structures of compounds E13 and E16 were determined by XRD studies. The in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory assessment of the compounds revealed that compounds showed considerable inhibitory activity. The substitute groups on the phenyl rings have an impact on the inhibitory activity of the compounds. Compound E08, containing an ester group on the phenyl ring, showed the highest inhibitory activity against BuChE (IC50: 97.97 ± 0.13 µM) compared to other compounds. According to the docking result, compound E08 exhibited higher binding affinity (-10.17 kcal/mol) against BuChE than the standard drug tacrine (-7.02 kcal/mol). Compound E08 was orientated towards the active site of the enzyme BuChE.Communicated by Ramaswamy H. Sarma.