Banca de DEFESA: LARISSA DE ALMEIDA PEIXOTO FERREIRA
Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.STUDENT : LARISSA DE ALMEIDA PEIXOTO FERREIRA
DATE: 16/04/2021
TIME: 09:00
LOCAL: Vídeo Conferência
TITLE:
Synthesis and pharmacological evaluation of new 3-(imidazo[1,2-a]pyridine)-coumarins designed for the treatment of Alzheimer's Disease
KEY WORDS:
Alzheimer's disease, Coumarins, Imidazo-pyridines, AChE and BuChE inhibitors
PAGES: 173
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:
Alzheimer's disease (AD) is a progressive neurodegenerative disease that has a complex pathogenesis, inducing memory loss and cognitive disorders, which usually present in old age. Coumarins and imidazopyridines (IM) are compounds with wide pharmacological activity and have several promising studies related to the treatment of AD acting on several targets such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), aggregation of β-amyloid plaques (Aβ) and between others. Thus, the general objective of this work is the synthesis of new 3- (imidazo [1,2-a] pyridin-2-yl) -coumarins, based on classic bioisosterism substitutions of 4- (dimethylamino) phenyl by imidazopyridines (IM) as possible cholinesterase inhibitors for possible treatment of AD. The first series is the synthesis of 3- (imidazo [1,2-a] pyridines) -coumarins (66a-d) involving 5 reaction steps. Through the synthesis of 3-acetyl-coumarins (67a-c) (70% to 90% yield) (step 1), α-bromination of 3-acetyl-coumarins (51 to 73% yield) (step 2) , formation of the IM nucleus (64 to 69% yield)(step 3), alkylation of the IMs with a conversion factor of 74% (66a) and 81% (66b) (step 4) and, finally, the amination step with the formation of the final compounds (66a-b). The second series is the synthesis of 3- (imidazo [1,2-a] pyridines-9'-ethylcarboxylate) -coumarins, involving Knoevenagel condensation to form compounds with coumarin nucleus (89) (86% yield) ( 1 step), o-alkylation (93a-d) (yields from 30 to 74%), forming the nuclei of the IMs (102a-d) (yields from 42 to 74%) and amination (103a-d) (yields from 31% to 79%). The compounds obtained were purified and then characterized by spectroscopic techniques (1H and 13C NMR). An initial screening was carried out at a fixed concentration of 30 μM, for two final compounds 66b and 103b, obtained initially by the non-optimized synthetic route, with an enzymatic inhibition of approximately 91.7% (AChE) / 92.4% (BuChE) and 98.1% (AChE) / 88.6% (BuChE), respectively. In addition to the activity, silicon studies of molecular modeling and ADME parameters were carried out. Based on these preliminary results, new compounds are being synthesized, and the IC50 and enzymatic kinetics against cholinesterases will be determined.
BANKING MEMBERS:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interno - 1735975 - CEDRIC STEPHAN GRAEBIN
Interna - 1979542 - RENATA BARBOSA LACERDA
Externa à Instituição - MARIA LETÍCIA DE CASTRO BARBOSA - UFRJ
Externa à Instituição - MARINA AMARAL ALVES - UFRJ