Synthesis, biological evaluation, and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

• Published in: Archiv der Pharmazie (Weinheim) 2018-04, Vol.351 (3-4), p.e1700273-n/a
• Main Authors: Uysal, Sirin, Parlar, Sulunay, Tarikogullari, Ayse H., Aydin Kose, Fadime, Alptuzun, Vildan, Soyer, Zeynep
• Format: Article
• Language: English
• Subjects: 2(3H)‐benzoxazolone; Acetylcholinesterase - metabolism; Animals; antioxidant activity; Benzoxazoles - chemical synthesis; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Butyrylcholinesterase - metabolism; cholinesterase inhibitors; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Crystallography, X-Ray; Dose-Response Relationship, Drug; Electrophorus; Horses; Mannich; Mannich Bases - chemical synthesis; Mannich Bases - chemistry; Mannich Bases - pharmacology; molecular docking; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201700273

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC50 = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC50 = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC50 = 1.04 ± 0.04 mM) than Trolox (IC50 = 1.50 ± 0.05 mM). A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory and antioxidant activities. Compound 7 exhibited the highest inhibition against the AChE enzyme, with an IC50 value of 7.53 ± 0.17 µM, and also had moderate antioxidant activity.