Design, Synthesis, Biological Evaluation, and Molecular Modeling of Substituted pyrrolo[2,1-a]isoquinolinones derivatives: Discovery of Potent Inhibitors of AChE and BChE

PARRAVICINI, OSCAR; ANGELINA, EMILIO; SPINELLI, ROQUE; GARIBOTTO, FRANCISCO; SIANO, ALVARO S. ; CABEDO, NURIA; CORTES, DIEGO; ENRIZ, RICARDO DANIEL

NEW JOURNAL OF CHEMISTRY

ROYAL SOC CHEMISTRY

Lugar: CAMBRIDGE; Año: 2021

1144-0546

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