Design, synthesis and biological evaluation of new benzoxazolone/benzothiazolone derivatives as multi-target agents against Alzheimer's disease.

Abstract

In this study, four series of compounds with benzoxazolone and benzothiazolone cores were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). Additionally, in order to shed light on the effect of the carbonyl groups of benzoxazolone/benzothiazolone, benzoxazole/benzothiazole-containing analogues were also synthesized and evaluated. Inhibition potency of all final compounds towards cholinesterase enzymes and their antioxidant activity were tested. Subsequently, the anti-inflammatory activity, cytotoxicity, apoptosis, and Aβ aggregation inhibition tests were also performed for selected compounds. The results indicated that compounds 11c, a pentanamide derivative with benzothiazolone core, and 14b, a keton derivative with benzothiazolone core, were considered as promising multi-functional agents for further investigation against AD. The reversibility, kinetic and molecular docking studies were also performed for the compounds with the highest AChE 14b (eeAChE IC50 = 0.34 μM, huAChE IC50 = 0.46 μM) and BChE 11c (eqBChE IC50 = 2.98 μM, huBChE IC50 = 2.56 μM) inhibitory activities.

• Authors: Merve Erdogan, Burcu Kilic, Rahsan Ilıkcı Sagkan, Fatma Aksakal, Tugba Ercetin, Hayrettin O Gulcan, Deniz S Dogruer
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 212 Pg. 113124 (Feb 15 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33395623 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Anti-Inflammatory Agents, Non-Steroidal
• Benzoxazoles
• Cholinesterase Inhibitors
• Neuroprotective Agents
• Protein Aggregates
• Thiazoles
• benzoxazolone
• Acetylcholinesterase
• Butyrylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid beta-Peptides (antagonists & inhibitors, metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Benzoxazoles (chemical synthesis, chemistry, pharmacology)
• Butyrylcholinesterase (metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Horses
• Humans
• Mice
• Molecular Structure
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Protein Aggregates (drug effects)
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)