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

PARRAVICINI, OSCAR; GARRO ADRIANA; GUTIERREZ LUCAS JOEL; ANDUJAR SEBASTIAN; ENRIZ, RICARDO D.

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

8,9-disubstituted pyrrolo[2,1-a]isoquinolin-3-ones derivatives, a newseries of AChE and BChE inhibitors. Design, synthesis and biologicalevaluation.Parravicini Oa, Garro Aa, Gutiérrez La, Garibotto Fa, Andujar Sa, Cabedo Nb, Enriz Raa - Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis; InstitutoMultidisciplinario de Investigaciones Biológicas (IMIBIO-SL-CONICET).b - Departamento de Farmacología, Facultad de Farmacia, Universidad de ValenciaWe have previously reported the synthesis of 8-substituted and 8,9-disubstitutedpyrrolo[2,1-a]isoquinolinones derivatives1. Some of these structures have a slightstructural resemblance with rivastigmine, a reversible cholinesterase inhibitor that isused to treat dementia. On the other hand we have recently reported new AChEinhibitors2 and we have conducted molecular modeling studies that allowed us tounderstand in some detail the molecular interactions involved in the stabilization ofdifferent inhibitor-enzyme complexes for this molecular target. Taking advantage of thisinformation, we asked ourselves if we would be able to design a new structure withinhibitory 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 adocking study; in the second one we performed simulations using molecular dynamicscalculations. 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 ourmolecular 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 synthesisof both compounds was carried out and then their inhibitory activities were evaluated. Asour simulations predicted both carbamates showed a remarkable inhibitory effect againstboth AChE and BChE. In fact, these compounds displayed stronger activity thanrivastigmine, the compound used as reference.References1Moreno, L.; Párraga, J.; Galan, A.; Cabedo, N.; Primo, J.; Cortes, D. Bioorg. med. chem.2012; 20(22):6589?6597.2Padrtova, T.; Marvanova, P.; Odehnalova, K.; Kubinova, R.; Parravicini, O.; Garro, A.;Enriz, R.; Humpa, O.; Oravec, M.; Mokry, P. Molecules. 2017; 22(12):2048.