Banca de DEFESA: LUCIANA LUIZ DE AZEVEDO

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
DISCENTE : LUCIANA LUIZ DE AZEVEDO
DATA : 27/12/2018
HORA: 13:00
LOCAL: Sala 50 PQ
TÍTULO:

DESIGN, DERIVATIZATION STUDIES AND PHARMACOLOGICAL EVALUATION OF N-METHYL-N-ACYLIDRAZONES PLANNED AS ENZYME PDE4 INHIBITORS

PALAVRAS-CHAVES:

PDE4, N-methyl-N-acylhydrazones, COPD, Buchwald-Hartwig reaction

PÁGINAS: 264
GRANDE ÁREA: Ciências Exatas e da Terra
ÁREA: Química
SUBÁREA: Química Orgânica
ESPECIALIDADE: Síntese Orgânica
RESUMO:

PDEs4 are described in the literature as phosphodiesterase enzymes wich acts in the regulation of cAMP levels and are directly involved in inflammatory processes control in the human body. This characteristic has made this enzyme a very attractive target for development of anti-inflammatory drugs and numerous PDE4 inhibitors have been described, such as N-methyl-N-acylhydrazones (N-methyl-NAHs). Therefore, this work aim at the synthesis, characterization and pharmacological evaluation of novel compounds N-methylNAH derivatives as inhibitors of the PDE4 enzyme, to determine the influence of substituents in different positions for: 1- obtaining hybrid molecules (series A, B and C) for the chronic obstructive pulmonary disease’s treatment (COPD), from the molecular hybridization of salmeterol, a β2 agonist and N-methyl-NAH compounds, described by our group as potent inhibitors of PDE4; and 2- to obtain new N-aryl derivatives (series D) for modulations of physico-chemical properties. All modifications were planned from molecular modeling studies with the N-methyl-NAH prototype. Final molecules of A, B and C series were synthesized in convergent route after obtaining the two main building blocks, salmeterol and N-methyl-NAHs. The synthesis of the N-methyl-NAHs block of A and B series was performed after five steps, presenting yields ranging from 40-99%. For the C series synthesis it was necessary to use an alternative synthetic route, which was performed after four steps and presented yields ranging from 54-99%. The salmeterol block synthesis was performed after three steps in yields ranging from 51-96%. Finally, the reaction for the union of the two building blocks was evaluated testing several reaction conditions. However, there was no success in obtaining the hybrid compounds of A, B and C series. Despite, PDE4 inhibitory activity tests were performed for compounds synthesized in the N-methyl-NAHs block, similar in steric to the proposed final derivatives. It was observed an excellent activity for the C-labeled compound, with 97.4% inhibition of the PDE4 at the concentration of 10μM, as predicted by docking experiments, where it behaved like the N-methyl-NAH prototype. However, for the A and B series the observed results of inhibitory activity (0% and 84.3% at 10 μM, respectively) diverged from the theoretical studies, which predicted a correct interaction for the A series, but ain't for B. The D series synthesis was designed in two main steps: the first one was the synthesis of brominated N-methyl-N-acylhydrazonic derivative after four steps, with yields ranged from 70-92%; and the second one was the cross-coupling reaction itself between the halide and different amines. After several tests with BuchwaldHartwig coupling reaction, the methodology using Pd2(dba)3 as source of palladium, XPhos as binder, K3PO4 as base and dioxane as solvent, at 100 ° C for 3 hours proved to be the most
promising. 14 different N-methyl-N-acylhydrazones were synthesized and characterized, in yields ranging from 40-90%. After the D series synthesis, some were selected according to their physico-chemical characteristics for the biological evaluation, and the results were excellent, with PDE4 inhibition varying in the range of 80.3-100.0% at 10μM . Furthermore, the biological activitie of the D series validate the results observed by the docking experiments, which demonstrated that the essential interactions between ligand and the target enzyme are still there. ance profile.

MEMBROS DA BANCA:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interno - 1220404 - CARLOS MAURICIO RABELLO DE SANTANNA
Interno - 1058758 - MARCO EDILSON FREIRE DE LIMA
Interno - 1979542 - RENATA BARBOSA LACERDA
Externo à Instituição - MARINA AMARAL ALVES - UFRJ
Externo à Instituição - RICARDO OLIMPIO DE MOURA - UEPB
Externo à Instituição - MARCIO CONTRUCCI SARAIVA DE MATTOS - UFRJ