resumo
Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 mu M. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 +/- 0.014 mu M). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.
palavras-chave
THIAZOLE; SUBSTITUTION; PHARMACOLOGY; NITROGEN; SYSTEM
categoria
Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology
autores
Laghchioua, FE; da Silva, CFM; Pinto, DCGA; Cavaleiro, JAS; Mendes, RF; Paz, FAA; Faustino, MAF; Rakib, E; Neves, MGPMS; Pereira, F; Moura, NMM
nossos autores
Filipe Alexandre Almeida Paz
Investigador Principal
Ricardo Faria Mendes
Investigador Júnioragradecimentos
The authors thank the University of Aveiro, FCT/MCTES for their financial support to the LAQV-REQUIMTE (LA/P/0008/2020 DOI https://doi.org/10.54499/LA/P/0008/2020, UIDP/50006/2020 DOI https://doi.org/10.54499/UIDP/50006/2020 and UIDB/50006/2020 DOI https://doi.org/10.54499/UIDB/50006/2020) through national funds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. The authors also thank the Sultan Moulay Slimane University. R.F.M. and F.P. gratefully acknowledge FCT for a Junior Research Position (CEECIND/00553/2017) and Assistant Research Position (CEECIND/01649/2021), respectively. We thank Chemaxon Ltd. for access to JChem, Reactor, and Marvin. C.F.M.S. also thanks FCT for his PhD grant PD/BD/135103/2017 and grant COVID/BD/151838/2021.