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Design, synthesis and biological evaluation of 2-Phenyl-4H-chromen-4-one derivatives as polyfunctional compounds against Alzheimer’s disease

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Abstract

Polyfunctional compounds comprise a novel class of therapeutic agents for the treatment of multi-factorial diseases. A series of 2-Phenyl-4H-chromen-4-one and its derivatives (5a–n) were designed, synthesized, and evaluated for their poly-functionality against acetylcholinestrase (AChE) and advanced glycation end products (AGEs) formation inhibitors against Alzheimer’s disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit AChE AGEs formation with additional radical scavenging activity. Especially, 5m, 5b, and 5j displayed the greatest ability to inhibit AChE (IC50 = 8.0, 8.2, and 11.8 nM, respectively) and AGEs formation (IC50 = 55, 79, and 54 µM, respectively) with good antioxidant activity. Molecular docking studies explored the detailed interaction pattern with active, peripheral, and mid-gorge sites of AChE. These compounds, exhibiting such multiple pharmacological activities, can be further taken a lead for the development of potent drugs for the treatment of Alzheimer’s disease.

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Abbreviations

ChE:

Cholinesterase

AD:

Alzheimer’s disease

AChE:

Acetylcholinesterase

AGEs:

Advanced glycation end products

CAS:

Catalytic active site

PAS:

Peripheral anionic site

ACh:

Acetylcholine

FDA:

Food and drug administration

OS:

Oxidative stress

ROS:

Reactive oxygen species

Aβ:

β-amyloid

RAGE:

Receptor for AGEs

DPPH:

1,1-diphenyl-2-picryl-hydrazyl

EWG:

Electron withdrawing groups

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Acknowledgements

We acknowledge the financial support from the “Indian Council of Medical Research (ICMR)”, New Delhi, for providing us Senior Research Fellowships (ICMR-SRF); Award nos. BIC/11(11)/2014 and BIC/11(02)/2013.

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Authors and Affiliations

  1. Molecular Modeling Lab, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India

    Man**der Singh, Maninder Kaur & Om Silakari

  2. Department of Chemistry, Punjabi University, Patiala, Punjab, 147002, India

    Bhawna Vyas

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  1. Man**der Singh
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  2. Maninder Kaur
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  4. Om Silakari
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Correspondence to Om Silakari.

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Singh, M., Kaur, M., Vyas, B. et al. Design, synthesis and biological evaluation of 2-Phenyl-4H-chromen-4-one derivatives as polyfunctional compounds against Alzheimer’s disease. Med Chem Res 27, 520–530 (2018). https://doi.org/10.1007/s00044-017-2078-4

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