New azole-derived hemiaminal ethers as promising acetylcholinesterase inhibitors: synthesis, X-ray structures, in vitro and in silico studies

Abstract

A new class of azole-derived hemiaminal ethers is designed as acetylcholinesterase (AChE) inhibitors. The synthesized compounds exhibited remarkable inhibitory activity against acetylcholine. Chiral hemiaminals (3d and 3i) based on (R)-menthoxymethyl group exhibit excellent inhibition with IC₅₀ values of 0.983 ± 1.41 and 1.154 ± 0.89 µM. Similarly, butoxymethyl derivatives 3a, 3f and 3h, also showed promising inhibition comparable to the standard drug, Donepezil. In silico studies were performed to understand the mode of interactions with the target proteins, where menthoxymethyl azoles 3d and 3i demonstrated the highest docking scores. Molecular dynamics simulations displayed the stable ligand–protein complex of 3i with effective binding interactions. The bioavailability and pharmacokinetic parameterssupported the suitability of these small molecule inhibitors to develop cost-effective drug leads for Alzheimer’s disease (AD). MTT assay substantiated the non-cytotoxic nature of the compounds. The synthesized compounds are extensively characterized by ¹H NMR, ¹³C NMR and mass spectral data and SC-XRD.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• acetylcholinesterase (AChE) inhibitors
• hemiaminal
• functionalized azoles
• Molecular docking
• MD simulation

Disclosure Statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

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Funding

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