1. Academic Validation
  2. Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3β

Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3β

  • Bioorg Med Chem Lett. 2024 Jun 19:110:129851. doi: 10.1016/j.bmcl.2024.129851.
Dingjun Wei 1 Jiaxin Cai 1 Feixia Qin 1 Qingqing Zhou 2 Wei Xiong 1 Chenshu Xu 1 Chenyang Li 3 Haiqiang Wu 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Shenzhen University Medical School, Shenzhen 518055, China.
  • 2 School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China.
  • 3 School of Pharmacy, Shenzhen University Medical School, Shenzhen 518055, China. Electronic address: lcy@szu.edu.cn.
  • 4 School of Pharmacy, Shenzhen University Medical School, Shenzhen 518055, China. Electronic address: wuhq@szu.edu.cn.
Abstract

Alzheimer's disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure-activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC50 = 1.22 μM), although the potency was increased by 2' substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3β-specific inhibitory activity (2, IC50 = 0.0021 μM), and the electron-withdrawing group and 2' and 3' substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14-35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R2). Increasing the linker length and introduction of a methoxy group (R2) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3β. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3β, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.

Keywords

Alzheimer’s disease; Dual inhibitor; GSK-3β; Glutaminyl cyclase; Hybrid; Structure-activity-relationship.

Figures
Products