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Chromone–lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities

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Abstract

Purpose

Alzheimer’s disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD.

Methods

Chromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD.

Results

The primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 μM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aβ aggregation and selectively chelate with copper ions in 2:1 M ratio.

Conclusion

Compound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aβ aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability.

Graphical abstract

A new chromone–lipoic acid hybrid was synthesized as anti-Alzheimer agent with BuChE inhibitory activity, anti-Aβ aggregation, metal-chelation and antioxidant properties.

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Acknowledgments

This work was supported by a grant from The National Institute for Medical Research Development (NIMAD, grant number: 971370).

Author information

Authors and Affiliations

  1. Biomaterials Group, Pharmaceutical Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran

    Leili Jalili-Baleh, Alireza Foroumadi & Mehdi Khoobi

  2. Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Hamid Nadri

  3. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

    Hamid Forootanfar

  4. Faculty of Pharmacy, Department of Biochemistry, Hacettepe University, Ankara, Turkey

    Tuba Tüylü Küçükkılınç & Beyza Ayazgök

  5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Toxicology and poisoning Research Centre, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Sharifzadeh

  6. Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran

    Mahban Rahimifard, Maryam Baeeri & Mohammad Abdollahi

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  1. Leili Jalili-Baleh
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  2. Hamid Nadri
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  11. Mehdi Khoobi
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Contributions

Leili Jalili-Baleh synthesized and characterized the compounds and participated in the writing of the manuscript. Hamid Nadri evaluated ChEs inhibition activity of the compounds, docking and kinetic studies. Hamid Forootanfar evaluated neuroprotective activity of the compounds. Tuba Tüylü Küçükkılınç and Beyza Ayazgök participated in intracellular ROS inhibition activity of the compound. Mahban Rahimifard and Maryam Baeeri performed FRAP assay. Mohammad Sharifzadeh, Mohammad Abdollahi and Alireza Foroumadi contributed to the characterization of the compounds, data analysis and revision of the manuscript. Mehdi Khoobi conceived the main idea of the study, organized the work and contributed to the overall analysis of the results. All the authors reviewed and approved the manuscript.

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Correspondence to Mehdi Khoobi.

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Jalili-Baleh, L., Nadri, H., Forootanfar, H. et al. Chromone–lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities. DARU J Pharm Sci 29, 23–38 (2021). https://doi.org/10.1007/s40199-020-00378-1

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