NEW AChE LIGANDS WITH CARBAMATE FUNCTION

PARRAVICINI O; JANETA SALTOS MV; VILA DASI L; CABEDO ESCRIG N

Valencia, España

Congreso; 8° Congreso de Estudiantes de Farmacia; 2018

Centro de Estudiantes de Farmacia de la Universidad de Valencia

Acetylcholinesterase enzyme (AChE) inhibitors are commercial drugs that counteract the evolution of Alzheimer Disease (AD). Several phenylcarbamates, such as rivastigmine, are of special interest in the pharmaceutical industries as they produce the pseudo-irreversible inhibition of AChE so that preventing the cholinergic deficit of advanced stages of AD. In this work, starting from docking and molecular dynamics (MD) studies, the synthesis of new isoquinolines carbamates potential antagonists of AChE was carried out.Docking studies were achieved using Autodock 4.0 program (X-ray structure of receptor code 1DX6, available at Protein Data Bank). For MD simulations AMBER program package was employed. Synthesis of isoquinoline derivatives was performed following similar pathways as previously reported by this workgroup.More than 20 isoquinoline carbamates were designed. A preliminary molecular modelling study for rivastigmine and proposed carbamates was made. It was established the spatial arrangement of each of the complexes under study and their corresponding bond energy. This analysis allowed to identify structures that would show similar behaviour to AChE commercial inhibitors. According to obtained results three series of carbamates were synthesized with a pirrolo[2,1-a]isoquinolin-3-one nucleus. Obtained derivatives were isolated and purified according to adequate chromatographic techniques and subsequently identified by 1H y 13C NMR. Our calculations suggested that certain proposed carbamates would present interactions with AChE active site similar to those observed in complexes of commercial inhibitors. It is expected to corroborate theoretical data through the in vitro evaluation of inhibitory capacity of the new compounds.