2. Academic Validation
  3. The structure-based optimization of δ-sultone-fused pyrazoles as selective BuChE inhibitors

The structure-based optimization of δ-sultone-fused pyrazoles as selective BuChE inhibitors

  • Eur J Med Chem. 2020 Sep 1;201:112273. doi: 10.1016/j.ejmech.2020.112273.
Ziwen Zhang 1,  Jingli Min 1,  Mengdie Chen 1,  Xia Jiang 1,  Yingying Xu 1,  Huali Qin 2,  Wenjian Tang 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, China.
  • 2 School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China. Electronic address: [email protected].
  • 3 School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, China. Electronic address: [email protected].
PMID: 32569925 DOI: 10.1016/j.ejmech.2020.112273
Abstract

Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with δ-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC50 = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (Ki = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis.

Keywords

Alzheimer’s disease; Cholinesterase; Pyrazole; Structural optimization; SuFEx; Sultone.

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