{"title":"含有马来酰亚胺和咪唑基团的谷氨酰胺酰环酶和糖原合酶激酶-3β双重抑制剂的结构-活性关系。","authors":"Dingjun Wei , Jiaxin Cai , Feixia Qin , Qingqing Zhou , Wei Xiong , Chenshu Xu , Chenyang Li , Haiqiang Wu","doi":"10.1016/j.bmcl.2024.129851","DOIUrl":null,"url":null,"abstract":"<div><p>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 (<strong>2</strong>, IC<sub>50</sub> = 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 (<strong>2</strong>, IC<sub>50</sub> = 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 <strong>14</strong>–<strong>35</strong> revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R<sup>2</sup>). Increasing the linker length and introduction of a methoxy group (R<sup>2</sup>) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of <strong>33</strong> and <strong>24</strong> 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.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3β\",\"authors\":\"Dingjun Wei , Jiaxin Cai , Feixia Qin , Qingqing Zhou , Wei Xiong , Chenshu Xu , Chenyang Li , Haiqiang Wu\",\"doi\":\"10.1016/j.bmcl.2024.129851\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 (<strong>2</strong>, IC<sub>50</sub> = 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 (<strong>2</strong>, IC<sub>50</sub> = 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 <strong>14</strong>–<strong>35</strong> revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R<sup>2</sup>). Increasing the linker length and introduction of a methoxy group (R<sup>2</sup>) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of <strong>33</strong> and <strong>24</strong> 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.</p></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-06-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24002531\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24002531","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3β
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.
期刊介绍:
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.