8,9-disubstituted pyrrolo[2,1-a]isoquinolin-3-ones derivatives, a new series of AChE and BChE inhibitors. Design, synthesis and biological evaluation.

OSCAR PARRAVICINI; ADRIANA D. GARRO; GUTIERREZ, L.G; FRANCISCO M. GARIBOTTO; SEBASTIÁN A. ANDUJAR; CABEDO, NURIA; DANIEL ENRIZ

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad de Biofísica Argentina; 2019

Sociedad Argentina de Biofísica

We have previously reported the synthesis of 8-substituted and 8,9-disubstituted pyrrolo[2,1-a]isoquinolinones derivatives1. Some of these structures have a slight structural resemblance with rivastigmine, a reversible cholinesterase inhibitor that is used to treat dementia. On the other hand we have recently reported new AChE inhibitors2 and we have conducted molecular modeling studies that allowed us to understand in some detail the molecular interactions involved in the stabilization ofdifferent inhibitor-enzyme complexes for this molecular target. Taking advantage of this information, we asked ourselves if we would be able to design a new structure with inhibitory effects of AChE, taking the pyrroloisoquinoline moiety as starting point. We conducted a molecular modeling study in four steps. In the first step we carried out a docking study; in the second one we performed simulations using molecular dynamics calculations. With these data, we performed a per-residue analysis and, in the last step, quantum mechanics calculations were made in order to evaluate in details the molecularinteractions that stabilize the different ligand-receptor complexes. Based on our molecular modeling study we designed two new structures: 8-chloro-9-phenylcarbamate-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-3-one and 8,9-diethylcarbamate-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-3-one. The synthesis of both compounds was carried out and then their inhibitory activities were evaluated. Asour simulations predicted both carbamates showed a remarkable inhibitory effect against both AChE and BChE. In fact, these compounds displayed stronger activity than rivastigmine, the compound used as reference.