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 IC
50 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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