Banca de DEFESA: MAYARA CARLA DOS SANTOS

NEW ACYLGUANIDINE QUINOLINES DESIGNED AS SELECTIVE BUTYRYLCHOLINESTERASE INHIBITORS

Alzheimer's disease; quinolines; acylguanidines butyrylcholinesterase inhibitors.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by a deficiency of intact cholinergic neurons. Butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) are nervous system enzymes that catalyze the hydrolysis of acetylcholine (ACh), reducing neurotransmitter levels and ending communication between nerve cells. AChE is still the main therapeutic target for the treatment of AD, however studies suggest an important role for BuChE in the hydrolysis of ACh in more advanced stages of AD, with selective BuChE inhibitors being seen as potential candidates for the treatment of this disease. This work describes a new series of quinolinic acylguanidines (59-62A-D; 63-66A-D) designed as selective inhibitors of BuChE. Structural design was based on the indole and bromopyrrolic acylguanidines previously described by our group, which were shown to be selective inhibitors of BuChE. In the new derivatives, the acylguanidine pharmacophore was maintained and, through bioisosterism, we propose the exchange of the main heterocycle for the quinoline nucleus with different substitution patterns in position two of the central heterocycle. The synthesis of the compounds was based on obtaining the key intermediates tert-butyl((methylthio)(quinoline-4-carboxamido) methylene) carbamates (58a-d) for subsequent condensation with the amines of interest (A-D) and subsequent reaction in an acidic medium to remove the protecting group ( N-Boc). 20 original compounds were synthesized, including protected (59-62-A-D) and free acylguanidines (63-66-A-D), characterized by H¹NMR and DEPTQ. The free phenyl-quinoline acylguanidines (64A-D) were identified as selective inhibitors of the BuChE enzyme (IC₅₀ between 7 and 12 µM). The two acylguanidines with the lowest IC₅₀ values for BuChE inhibition (64C-D) were evaluated for their antioxidant profile in the DPPH model, but showed no activity at tested concentration (110µM). Molecular docking studies made it possible to understand the possible modes of interaction of active compounds with BuChE and in silico prediction of ADME and druglike properties suggests that the new quinolinic acylguanidines have a good pharmacokinetic profile.