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

• Published in: Journal of biomolecular structure & dynamics 2023-12, Vol.41 (24), p.15535-15548
• Main Authors: Nisar, Muhammad, Gondal, Humaira Yasmeen, Cheema, Zain Maqsood, Yousaf, Sammer, Nadeem, Humaira
• Format: Article
• Language: English
• Subjects: acetylcholinesterase (AChE) inhibitors; Alzheimer's disease; functionalized azoles; hemiaminal; MD simulation; Molecular docking
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2023.2190805

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 IC 50 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 1 H NMR, 13 C NMR and mass spectral data and SC-XRD. Communicated by Ramaswamy H. Sarma