Synthesis of benzylidene-benzofuranone derivatives as probes for detection of amyloid fibrils in cells

Abstract

Aggregated protein is the common cause of a wide variety of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, etc. It is proven that protein aggregation like amyloid β (Aβ) is one of the critical factors causing AD and, its diagnosis in the early stages of the disease is important for the treatment or prevention of AD. To have a better understanding of protein aggregation and its pathologies, there is a huge need to design and develop new and more trustworthy probe molecules for in vitro amyloid quantification and in vivo amyloid imaging. In this study, 17 new biomarker compounds, have been synthesized from benzofuranone derivatives, to detect and identify amyloid in vitro (dye-binding assay) as well as in the cell by staining method. According to the results, some of these synthetic derivatives can be considered suitable identifiers and quantifiers to detect amyloid fibrils in vitro. Compared to thioflavin T, 4 probes out of 17 probes have shown good results in selectivity and detectability of Aβ depositions, and their binding properties were also confirmed with in silico analysis. The drug-likeness prediction results for selected compounds by the Swiss ADME server show a satisfactory percentage of blood-brain barrier (BBB) permeability and gastrointestinal (GI) absorption. Among all of them, compound 10 was able to show better binding properties than others, and in vivo study showed that this compound was capable of detecting intracellular amyloid.

Communicated by Ramaswamy H. Sarma

Keywords:

• Neurodegenerative diseases
• Amyloid β
• Insulin
• Benzylidene derivatives
• Benzofuranone derivatives

Acknowledgements

The authors gratefully acknowledge Alzahra Uiversity and Research Council of Kermanshah University of Medical Sciences for the financial support. The author thanks Ms. Kimia Ahadi Amandi for docking study and Dr. Nadia Karimi for help in analysis the FTIR, NMR and MS information. We also thank Dr. Leila Hosseinzadeh for assisting with the MTT assay.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Kermanshah University of Medical Sciences under code No. IR.KUMS.REC.1398.152.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author contributions

S.A.G., and H.A. designed research; M.T., and H.A. synthesize the compounds; M.T. and S.A.G. performed research; S.A.G., M.T. and H.A. analyzed data; and S.A.G., M.T., and H.A. wrote the paper. S.A.G., H.A., and H.O.G. helped for methodology and resource. All authors read and approved the final manuscript.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.