Design, synthesis, biological evaluation and molecular modelling of substituted pyrrolo[2,1-a]isoquinolinone derivatives: discovery of potent inhibitors of AChE and BChE

Abstract

We report here the design, synthesis and biological evaluation of a new series of substituted pyrrolo[2,1-a]isoquinolin-3-one derivatives, some of which have strong inhibitory activity against both AChE and BChE enzymes. The design of these new inhibitors was carried out taking rivastigmine as the starting structure. Thus, on the basis of an exhausting molecular modeling study using combined techniques (docking, dynamic molecular simulations and QTAIM calculations), we obtained new ligands possessing stronger inhibitory effects than rivastigmine, the reference compound. QTAIM analysis gave us detailed information about the molecular interactions stabilizing the different ligand–enzyme complexes. These calculations showed the importance of the interaction with the CAS esteratic site for the inhibitory effect of these compounds. Nevertheless, they also indicated that the combination of interactions with CAS and strong interactions with the PAS site might be beneficial for the inhibitory effect.