Banca de DEFESA: NATHALIA FONSECA NADUR

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : NATHALIA FONSECA NADUR
DATE: 10/07/2025
TIME: 09:00
LOCAL: Virtual (on line)
TITLE:

Structural Optimization of 7-((piperidin-1-yl)alkoxy)-coumarins: Homologation and Construction of Mimetic Heterocycles Aiming at the Development of Novel Mixed Cholinesterase Inhibitors

KEY WORDS:

Keywords: Alzheimer, cholinesterase inhibitors, multitarget.

PAGES: 271
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:

Alzheimer's disease (AD) is characterized by being a progressive and irreversible neurodegenerative disorder of memory and other cognitive functions, affecting occupational and social functioning. The use of compounds involving multitarget-directed ligands (MTDLs), such as mixed inhibitors of the enzyme acetylcholinesterase (AChE) that indirectly suppress aggregation of β-amyloid (Aβ) or combine cholinesterase (ChEs) inhibition with other mechanisms, has been observed as a high-value objective for AD treatment due to possibility to inhibit simultaneously different targets that contribute to installation and maintenance of the disease. Recently, our research group (LaDMol-QM) described two classes of coumarins (22 and 23a-b) that exhibited mixed inhibitory activity, acting on both CAS and PAS simultaneously, with IC50 values of up to 20 nM on AChE and selectivities of up to 354-fold on butyrylcholinesterase (BChE). Based on the pharmacophoric map of these series, this work has as its general objective the design, synthesis, and pharmacological evaluation of a series of benzyl-triazole-coumarins and coumarin mimetic heterocycles as possible mixed inhibitors of the AChE enzyme. Three series were proposed: the first, an optimization of the triazole-coumarin series involving the synthesis of new benzyl derivatives (series A); the second, a series with mimetic heterocycles, including quinolinone (series B) and aminoquinazoline (series C). The synthesis of series A, a superior homolog of series 23, was completed after ten synthetic steps, leading to the production of tem new derivatives of the triazole-coumarin series (24a-j), in which all compounds were able to inhibit AChE with IC50 values ranging from 4.2 to 103.8 nM and selectivities of up to 685-fold against BChE. The molecular docking study showed consistency with the results of the enzymatic kinetics study of triazole-coumarin compounds, which classified them as mixed-type inhibition. The multitarget potential of series A was demonstrated by the results obtained against hH3R, MAO-A, and MAO-B. The synthesis of series B, a classical bioisostere of series 22, was completed after six synthetic steps, leading to the production of seven new quinolinone derivatives (56a-g), which demonstrated a dual inhibition profile of cholinesterases (ChEs). Molecular docking studies elucidated the distinct inhibition mechanisms observed for the B series derivatives. The synthesis of the C series, a non-classical bioisostere of the 22 series, was performed in a convergent manner after obtaining the two main reaction building blocks, phenol-2-amino quinazoline and chloroalkyl piperidine hydrochloride, leading to the production of two new derivatives of the amino quinazoline series (65a-b), which were shown to be capable of inhibiting BChE. The molecular docking study showed consistency with the results of the enzyme kinetics study, which classified them as mixed-type inhibition.

COMMITTEE MEMBERS:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interna - ***.742.388-** - AUREA ECHEVARRIA AZNAR NEVES LIMA - UFRRJ
Interno - 1220404 - CARLOS MAURICIO RABELLO DE SANT ANNA
Interno - 2624418 - CLAUDIO EDUARDO RODRIGUES DOS SANTOS
Externo à Instituição - PEDRO DE SENA MURTEIRA PINHEIRO - UFRJ
Externa à Instituição - MARINA AMARAL ALVES - UFRJ
Externo à Instituição - GUILHERME DA SILVA CALEFFI - UFRJ