Synthesis and Molecular Docking Studies of 5-Trifluoromethoxy-2-Indolinones as Cholinesterase Dual Inhibitors

Abstract

Background:

In Alzheimer’s disease, butyrylcholinesterase (BuChE) activity gradually increases, while acetylcholinesterase (AChE) activity decreases or remains unchanged. Dual inhibitors have important roles in regulation of synaptic acetylcholine levels and progression of Alzheimer’s disease.

Methods:

1-(Thiomorpholin-4-ylmethyl)/benzyl-5-trifluoromethoxy-2-indolinones (6–7) were synthesized. AChE and BuChE inhibitory effects were investigated with Ellman’s method. Molecular docking studies were performed for analyzing the possible binding interactions at active sites.

Results:

Compound 6g was the strongest inhibitor against both AChE (K_i = 0.35 μM) and BuChE (K_i = 0.53 μM). It showed higher inhibitory effects than both donepezil and galantamine. Moreover, compound 7m had a higher inhibitory effect than galantamine and the effect was comparable to that of donepezil against both AChE (K_i = 0.69 μM) and BuChE (K_i = 0.95 μM).

Conclusion:

The benzyl substitution compared with 1-(thiomorpholin-4-ylmethyl) group significantly increased both AChE and BuChE inhibitory effects.

Keywords::

• 5-trifluoromethoxy-2-indolinones
• acetylcholinesterase inhibitors
• butyrylcholinesterase inhibitors
• hydrazinecarbothioamide
• molecular docking

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.4155/fmc-2023-0281

Author contributions

Concept: Ö Soylu-Eter, N Özsoy and N Karalı. Design: Ö Soylu-Eter, N Özsoy and N Karalı. Supervision: N Özsoy and N Karalı. Resources: N Özsoy and N Karalı. Materials: N Özsoy and N Karalı. Data collection and/or processing: Ö Soylu-Eter and N Özsoy. Analysis and/or interpretation: Ö Soylu-Eter, N Özsoy and N Karalı. Literature search: Ö Soylu-Eter, N Özsoy and N Karalı. Writing: Ö Soylu-Eter, N Özsoy and N Karalı. Critical reviews: Ö Soylu-Eter, N Özsoy and N Karalı.

Acknowledgments

The authors are grateful to the Abdi İbrahim A.Ş., for supplying donepezil.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Comepting interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.