Banca de DEFESA: LETICIA BERSOT DE OLIVEIRA

NEW INDOLE ACYLGUANIDINES DESIGNED AS SELECTIVE BUTYRYLCHOLINESTERASE INHIBITORS

Alzheimer, cholinesterase inhibitors, indol, acylguanidines

Alzheimer's Disease (AD) is a neurodegenerative disorder that affects memory and motor functions, being considered a multifactorial disease of undetermined origin. The main therapeutic strategy for the treatment of AD is the use of anticholinesterase drugs, inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The present work aims at the structural design, synthesis, characterization, in vitro and in silico evaluation of a new series of 1H-indole-2-acylguanidinic derivatives designed as candidates for cholinesterase inhibitors. The proposed derivatives were designed through the bioisosteric exchange of the 4,5-dibromopyrrole nucleus, present in the selective inhibitors of BuChE described in Goulart’s doctoral thesis (2021), by the indole aromatic heterocycle. The synthesis of derivatives was based on obtaining the key intermediate tert-butyl-(1H-indol-2-carboxamido)(methylthio)methylene)carbamate through the reaction between indolic acid chloride and mono-protected isomethylthiourea and later condensation with benzylamines of interest, followed by removal of the protection group in an acidic medium. The products were characterized by ¹H and ¹³C NMR. In vitro screening of AChE and BuChE inhibition highlighted the best products (28c) and (28d) as selective inhibitors of BuChE, which inhibited BuChE activity by more than 60% at a concentration of 30 µM and with an IC₅₀ of 5.997 and 5.498 µM, respectively. The structure-activity relationship corroborated previous results that already pointed to the importance of the free acylguanidine function for the inhibition of BuChE, and also indicates that the presence of bromo substituents in the heteroaromatic ring seems to be important for the activity of these derivatives, which still needs to be proven from the evaluation of brominated indole analogues. Additionally, halogenated substituents on the benzyl ring of acylguanidine favored anti-BuChE activity. Using the SwissADME tool, it was possible to predict that the new acylguanidines have good pharmacokinetic potential. Molecular docking studies carried out made it possible to understand the possible modes of interaction of compounds with BuChE. As perspectives, we have the proposition of new analogues of the series obtained for its optimization, as well as for a better understanding of the structure-activity relationship. The results showed that the structural planning was successful, but there was no optimization regarding the enzymatic activity. As future perspectives, we carry out assays of antioxidant activity and complexation with metals, in addition to proposing new analogues in an attempt to optimize the anti-BuChE activity, as well as for a better understanding of the structure-activity relationship. Additionally, we intend to investigate other pharmacological targets for the indole and dibromopyrrolic acylguanidines.