Design, synthesis, anti-acetylcholinesterase evaluation and molecular modelling studies of novel coumarin-chalcone hybrids

Abstract

The major enzyme responsible for the hydrolytic breakdown of the neurotransmitter acetylcholine (ACh) is acetylcholinesterase (AChE). Acetylcholinesterase inhibitors (AChEIs) are the most prescribed class of medications for the treatment of Alzheimer’s disease (AD) and dementia. The limitations of available therapy, like side effects, drug tolerance, and inefficacy in halting disease progression, drive the need for better, more efficacious, and safer drugs. In this study, a series of fourteen novel chalcone-coumarin derivatives (8a-n) were designed, synthesized and characterized by spectral techniques like FT-IR, NMR, and HR-MS. Subsequently, the synthesized compounds were tested for their ability to inhibit acetylcholinesterase (AChE) activity by Ellman’s method. All tested compounds showed AChE inhibition with IC₅₀ value ranging from 0.201 ± 0.008 to 1.047 ± 0.043 μM. Hybrid 8d having chloro substitution on ring-B of the chalcone scaffold showed relatively better potency, with IC₅₀ value of 0.201 ± 0.008 μM compared to other members of the series. The reference drug, galantamine, exhibited an IC₅₀ at 1.142 ± 0.027 μM. Computational studies revealed that designed compounds bind to the peripheral anionic site (PAS), the catalytic active site (CAS), and the mid-gorge site of AChE. Putative binding modes, ligand-enzyme interactions, and stability of the best active compound are studied using molecular docking, followed by molecular dynamics (MD) simulations. The cytotoxicity of the synthesised derivatives was determined using the MTT test at three concentrations (100 g/mL, 500 g/mL, and 1 mg/mL). None of the chemicals had a significant effect on the body at the highest dose of 1 mg/mL.

Communicated by Ramaswamy H. Sarma

Keywords:

• Acetylcholinesterase
• coumarin
• chalcone
• cytotoxicity
• molecular modelling

Author contributions

Joazaizulfazli Jamalis, Sankaranarayanan Murugesan and Subhash Chander-supervision, investigation and critical review; Basundhara Das, Subhrajit Biswas, Sonam Shakya and Mohammad Rizki Fadhil Pratama-methodology, software’s, investigation, formal analysis, data curation, interpretation of data and revision; Faiq H.S. Hussain, Shajarahtunnur Jamil and Aso Hameed Hasan, design of study, methodology, investigation, and original draft. All authors critically reviewed and approved the manuscript before submission.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors would like to express their gratitude to Universiti Teknologi Malaysia (UTM) and the Ministry of Higher Education (MOHE) Malaysia for sponsoring this research through the Fundamental Research Grant Scheme (FRGS/1/2019/STG01/UTM/02/7).