IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Synthesis of novel chalcones with monoamine oxidase inhibitory effects
Autor/es:
MARDER M; COLETTIS N; KNEZ D; GOBEC S; KAMECKI F
Lugar:
C.A.B.A
Reunión:
Congreso; Reunión Conjunta de las Sociedades de Biociencias; 2017
Institución organizadora:
SAIC, SAIB, SAI, SAFE, SAP, SAB, SAFIS, SAA, SAH
Resumen:
Monoamine oxidase (MAO) is a flavin adenine dinucleotide (FAD) containing enzyme bound to mitochondrial outer membranes of the cells. MAO consists of two isoforms, MAO-A and MAO-B. Due to their fundamental roles in the metabolism of biogenic amines, both MAO isoforms are of considerable pharmacological interest. In the central nervous system (CNS), MAO-A metabolizes serotonin and norepinephrine. Deficiency of these two neurotransmitters is associated with the development of depression. Oxidative deamination catalyzed by MAO-B is one of the major pathways of dopamine degradation in the human brain. MAO-B is therefore a target for the treatment of Parkinson?s disease (PD). Our aim is to contribute with novel MAO inhibitory compounds for the treatment of this CNS pathologies.In this work, we synthetized by aldol condensation, purified, and identified (MS and 1H/13C NMR spectra) a series of 27 chalcones (1,3- diphenyl-2-propen-1-one) based on structure activity relationship (SAR) studies of our previously synthetized chalcones and bibliography.The inhibitory activity of the compounds was evaluated in a fluorimetric assay by their effects on the production of hydrogen peroxide (H2O2) from p-tyramine by recombinant hMAOA and hMAOB. H2O2 was detected using Amplex Red reagent in the presence of horseradish peroxidase, where resorufin, a fluorescent product, is produced at stoichiometric amounts. The series of chalcone derivatives presented herein selectively inhibited hMAO-B (IC50 values ranged between 30 nM to 70 µM). 5?-chloro-2´-hydroxy-3-nitrochalcone; 4´,5´-dimethyl-2´-hydroxy-3-nitrochalcone; 5?-bromo-2´-hydroxy-3-nitrochalcone and 5?,3-dichloro-2´-hydroxychalcone were the most active ones (IC50= 29.4 ± 4.1 nM; 69.3 ± 11.9 nM; 74.2 ± 8.1 nM and 87.9 ± 6.0 nM, respectively).Our series of chalcone derivatives represent a promising contribution for the development of novel drugs for the treatment of PD.