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  3. Fragment-informed SAR: rational construction of quinoline derivatives as dual AChE/BChE inhibitors

Fragment-informed SAR: rational construction of quinoline derivatives as dual AChE/BChE inhibitors

  • Bioorg Chem. 2025 Aug:163:108747. doi: 10.1016/j.bioorg.2025.108747.
Dingkang Sun 1,  Huanglei Bi 2,  Lisha Ma 3,  Yuanyuan Zhu 3,  Hui-Fang Nie 3,  An Liu 4,  Yuhang Li 3,  Li Luo 5,  Xueying Liu 6,  Minggao Zhao 7,  Zhao Wei 8
Affiliations

Affiliations

  • 1 Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an 710038, China; Department of Medicinal Chemistry, School of Pharmacy, Air Force Medical University, Xi'an 710032, China.
  • 2 Department of Pharmacy, The 969th Hospital of the joint logistics support force of PLA, Hohhot 010051, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Air Force Medical University, Xi'an 710032, China.
  • 4 Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an 710038, China.
  • 5 Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an 710038, China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, Air Force Medical University, Xi'an 710032, China. Electronic address: wqwlxy@fmmu.edu.cn.
  • 7 Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an 710038, China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China. Electronic address: minggao@fmmu.edu.cn.
  • 8 Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an 710038, China; Department of Medicinal Chemistry, School of Pharmacy, Air Force Medical University, Xi'an 710032, China. Electronic address: weizhaobruce@163.com.
PMID: 40682972 DOI: 10.1016/j.bioorg.2025.108747
Abstract

This study introduces a Fragment-Informed Structure-Activity Relationship (FI-SAR) paradigm for developing cholinesterase inhibitors through strategic coupling of amino-functionalized fragments with quinoline scaffolds. A library of 105 conjugates was synthesized and comprehensively assessed to delineate fragment-to-conjugate activity transfer. Quantitative analysis revealed a positive correlation between fragment potency and conjugate inhibitory activity, with phenolic Mannich base derivatives showing the strongest interdependence. Notably, representative conjugate L4R1-3 achieved sub-nanomolar AChE inhibition (IC₅₀ = 4.6 nM), outperforming clinical references such as donepezil. Furthermore, dual-target inhibitors were constructed (e.g., L1-3, AChE/BChE IC₅₀ = 8.1/0.58 μM) by using FI-SAR strategy. Molecular simulations confirmed stable binding modes of high-activity conjugates within the AChE/BChE active site. This work establishes a streamlined FI-SAR framework, emphasizing that strategic fusion of privileged pharmacophores (e.g., phenolic Mannich Bases) with versatile scaffolds like quinoline can accelerate multi-target drug discovery, suggesting broader applicability to enzyme-driven diseases.

Keywords

Acetylcholinesterase; Fragment-informed structure–activity relationship (FI-SAR); Inhibitor; Phenolic Mannich base; Quinoline.

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