第十五届海洋药物学术年会暨2021国际海洋药物研讨会

74 / 2021-10-10 20:30:00

Discovery of Quinazolinone Derivatives as Novel Acetylcholinesterase (AchE) Inhibitors via Scaffold Hopping

Quinazolinone deviratives,AchE inhibitors,scaffold hopping

As the primary cause of dementia, Alzheimer’s disease (AD) is affecting more than 50 million people all over the world.¹ Although there are four approved acetylcholinesterase (AchE) inhibitors and one N-methyl-D-aspartate (NMDA) receptor antagonist available in market, they can just provide modest symptomatic relief without blocking the progression of the disease let alone the side effects.² Development of new more effective AchE inhibitors are still needed as safe and efficient AD therapeutics. Based on the co-crystal structure of Donepezil and AchE (PDB code: 6o4w),³ we designed a new series of quinazolinones (privileged scaffolds in marine natural products) as AchE inhibitors via a scaffold hopping strategy. Compounds MR2938 and MR2937 exhibited inhibitory activity against AchE with the IC₅₀ values of 5.5 and 5.8 μM, respectively. Molecular docking study showed that MR2937 mimic Donepezil and occupy the active site very well, whereas different from Donepezil, multiple π-π stacking and cation-π interactions rather than hydrogen bonds were observed. This may explain their discrepancy on AchE inhibitions and give hints on how to improve the in vitro activities next step. Structural modifications and biological evaluations using orthogonal assays are ongoing.



Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 41830535; 4217060347; 81874300; 81673350), and the Taishan Scholars Program, China.

References:

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2. Marucci, G.; Buccioni, M.; Ben, D. D.; Lambertucci, C.; Volpini, R.; Amenta, F. Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology 2021, 190, 108352.

3. Gerlits, O.; Ho, K. Y.; Cheng, X.; Blumenthal, D.; Taylor, P.; Kovalevsky, A.; Radic, Z. A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies. Chem. Biol. Interact. 2019, 309, 108698.