Design, synthesis, molecular docking and biological evaluation of β-carboline derivatives as cholinesterase inhibitors

• Published in: Journal of molecular structure 2023-02, Vol.1273, p.134291, Article 134291
• Main Authors: Baréa, Paula, Yamazaki, Diego Alberto dos Santos, Lima, Diego de Souza, Seixas, Flavio Augusto Vicente, da Costa, Willian Ferreira, Gauze, Gisele de Freitas, Sarragiotto, Maria Helena
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Benzoylpiperazine; Benzylpiperazine; Butyrylcholinesterase; Virtual screening; β-carboline
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.134291

•A set of β-carbolines were designed and subjected to virtual screening in AChE.•Nine selected compounds were synthesized and evaluated against AChE and BuChE.•Compound 4d (IC50 = 3.2 µM) displayed the highest inhibition of AChE.•Compounds 1a-c exhibited potent inhibition of BuChE, with IC50 of 0.6 to 0.9 µM.•Kinetic and docking molecular studies were performed for 1a and 4d. A set of novel β-carboline derivatives were designed and subjected to virtual screening studies by molecular docking in AChE. Among the compounds investigated, derivatives 1a-c, 2a, 3d-f and 4d,e showed lower scores than donepezil (reference compound) and reproducibility in Autodock and Autodock Vina programs. These derivatives were synthesized and evaluated in vitro against AChE and BuChE. The derivatives 4d and 4e displayed the highest inhibition of AChE, with IC50 values of 3.2 ± 0.4 µM and 4.8 ± 0.1 µM, respectively, while 1a-c were the best inhibitors of BuChE, displaying IC50 values of 0.6, 0.9 and 0.8 µM, respectively. Kinetic studies indicated that 1a and 4d are AChE inhibitors of mixed type, and BuChE inhibitors of mixed and competitive types, respectively. Molecular docking studies showed that 1a and 4d interacted similarly with the peripheral anionic and catalytic active sites of AChE while only 4d exhibited interaction by hydrogen bonding with Ser198 of the catalytic triad of BuChE, which confirmed the modes of inhibition of 1a and 4d obtained in the kinetic studies. Our results demonstrate that the strategies used to design and select novel compounds were efficient in the development of new AChE/BuChE dual-targeted inhibitors. [Display omitted]