Molecular modeling, synthesis and biological evaluation of arylamino-propanone derivatives as potential cholinesterases inhibitors

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

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

Molecular modeling, synthesis and biological evaluation ofarylaminopropanone derivatives as potential cholinesterases inhibitorsGarro Aa, Gutiérrez La, Parravicini Oa, Rojas Sa, Hudcova Ab, Kroutil Ab, Enriz Raa - Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis; InstitutoMultidisciplinario de Investigaciones Biológicas (IMIBIO-SL-CONICET).b - Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and PharmaceuticalSciencesA series of novel arylaminopropanone hydrochloride salts with carbamate moiety wassynthesized and evaluated as potential AChE and BChE inhibitors. In vitro measurementswere performed, and the results were compared with those obtained for galanthamineand rivastigmine, drugs currently used in the treatment of neurodegenerative diseases.The most potent compounds, displayed inhibitory activity against AChE in vitro. Theirpercentage inhibition of AChE was comparable to galanthamine and higher torivastigmine, with IC50 in micromolar range. The structure-activity relationship showsthat the incorporation of a piperidine moiety leads to higher inhibitory activity. Incomparison, the replacement of piperidine by morpholine significantly decreased theactivity against both enzymes. Our results also revealed that compounds with longeralkylamine moiety have higher activity and selectivity to BChE.The molecular modeling study indicates that these compounds bind to the same activesite of AChE as galanthamine, although some other strong molecular interactions wereobserved. Some of the molecular interactions obtained for the compounds reported hereare a little weaker than those found for galanthamine, which would indicate a possiblelower affinity for active site of AChE. The differences in activity of piperidine-substitutedfrom alkyl-substituted compounds can be explained by distinct spatial orientation of thebasic nitrogen in amine closed in a ring-substructure and amine with alkyl chains.Although the inhibitory activities of these compounds are slightly weaker to those ofgalanthamine, these compounds show promising potential. They can be taken as startingstructures for further molecular modeling and synthetic research.