Molecular modeling, synthesis and biological evaluation of arylaminopropanone derivatives as potential cholinesterases inhibitors

PARRAVICINI, OSCAR; ROJAS, SEBASTIÁN; GARRO, ADRIANA

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

A series of novel arylaminopropanone hydrochloride salts with carbamate moiety was synthesized and evaluated as potential AChE and BChE inhibitors. In vitro measurements were performed, and the results were compared with those obtained for galanthamine and rivastigmine, drugs currently used in the treatment of neurodegenerative diseases.The most potent compounds, displayed inhibitory activity against AChE in vitro. Their percentage inhibition of AChE was comparable to galanthamine and higher to rivastigmine, with IC 50 in micromolar range. The structure-activity relationship shows that the incorporation of a piperidine moiety leads to higher inhibitory activity. In comparison, the replacement of piperidine by morpholine significantly decreased theactivity against both enzymes. Our results also revealed that compounds with longer alkylamine moiety have higher activity and selectivity to BChE. The molecular modeling study indicates that these compounds bind to the same active site of AChE as galanthamine, although some other strong molecular interactions were observed. Some of the molecular interactions obtained for the compounds reported here are a little weaker than those found for galanthamine, which would indicate a possible lower affinity for active site of AChE. The differences in activity of piperidine-substituted from alkyl-substituted compounds can be explained by distinct spatial orientation of the basic 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 of galanthamine, these compounds show promising potential. They can be taken as starting structures for further molecular modeling and synthetic research.