Pub Date : 2026-01-04DOI: 10.1016/j.ejmech.2026.118559
Xiaojuan Yang , Guoyang Ma
Cancer is a major health issue worldwide, necessitating the development of novel treatments because treating this disease is challenging. Napabucasin, a furan-fused 1,4-naphthoquinone, exhibits significant anticancer activity through various molecular mechanisms and has become a privileged scaffold for developing antitumor therapeutics. In this review, we systematically evaluated recent progress in the use of napabucasin as a privileged scaffold for the discovery of antitumor drugs, focusing on structure-activity relationships (SARs), structural modification strategies, and the illustration of tumor inhibitory pathways from a mechanistic perspective. By conducting multidimensional assessments, we propose feasible directions for developing napabucasins with improved pharmacological properties for cancer treatment.
{"title":"Recent progress of napabucasin as privileged scaffold in the discovery of anticancer agents","authors":"Xiaojuan Yang , Guoyang Ma","doi":"10.1016/j.ejmech.2026.118559","DOIUrl":"10.1016/j.ejmech.2026.118559","url":null,"abstract":"<div><div>Cancer is a major health issue worldwide, necessitating the development of novel treatments because treating this disease is challenging. Napabucasin, a furan-fused 1,4-naphthoquinone, exhibits significant anticancer activity through various molecular mechanisms and has become a privileged scaffold for developing antitumor therapeutics. In this review, we systematically evaluated recent progress in the use of napabucasin as a privileged scaffold for the discovery of antitumor drugs, focusing on structure-activity relationships (SARs), structural modification strategies, and the illustration of tumor inhibitory pathways from a mechanistic perspective. By conducting multidimensional assessments, we propose feasible directions for developing napabucasins with improved pharmacological properties for cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118559"},"PeriodicalIF":5.9,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1016/j.ejmech.2025.118548
Song Chen , Hongjin Zhai , Shuhan You, Bin Zhang, Gui Lu
The quinazoline-based Aurora kinase inhibitor 9h, previously developed by our group, exhibited potent efficacy both in vitro and in vivo. However, its further development was hindered by a short half-life and insufficient metabolic stability. To address these limitations, we employed machine learning-driven in silico models to predict 9h′s key metabolic sites. Based on these predictions, electronic isosteric substitutions and metabolic blocking strategies were employed to optimize these sites, yielding a series of new quinazoline derivatives. Subsequent liver microsomal stability assays identified compound 4q as the lead candidate, exhibiting significantly enhanced metabolic stability with a 14-fold and 4.5-fold increase in half-life relative to 9h in rat and human microsomes, respectively. Pharmacokinetic evaluation in rats revealed 4q possesses a favorable profile, with an oral half-life of 5.5 h, an intravenous half-life of 4.1 h, and an oral bioavailability of 58 %. Importantly, 4q maintained potent inhibitory activity in vivo, achieving a tumor growth inhibition rate of 56.7 %, consistent with its robust in vitro efficacy. Molecular docking simulations further elucidated 4q′s binding mode with Aurora kinase, providing a structural basis for its activity.
{"title":"Computer-Aided optimization of quinazoline-based Aurora kinase inhibitors for enhanced metabolic stability","authors":"Song Chen , Hongjin Zhai , Shuhan You, Bin Zhang, Gui Lu","doi":"10.1016/j.ejmech.2025.118548","DOIUrl":"10.1016/j.ejmech.2025.118548","url":null,"abstract":"<div><div>The quinazoline-based Aurora kinase inhibitor <strong>9h</strong>, previously developed by our group, exhibited potent efficacy both <em>in vitro</em> and <em>in vivo</em>. However, its further development was hindered by a short half-life and insufficient metabolic stability. To address these limitations, we employed machine learning-driven <em>in silico</em> models to predict <strong>9h</strong>′s key metabolic sites. Based on these predictions, electronic isosteric substitutions and metabolic blocking strategies were employed to optimize these sites, yielding a series of new quinazoline derivatives. Subsequent liver microsomal stability assays identified compound <strong>4q</strong> as the lead candidate, exhibiting significantly enhanced metabolic stability with a 14-fold and 4.5-fold increase in half-life relative to <strong>9h</strong> in rat and human microsomes, respectively. Pharmacokinetic evaluation in rats revealed <strong>4q</strong> possesses a favorable profile, with an oral half-life of 5.5 h, an intravenous half-life of 4.1 h, and an oral bioavailability of 58 %. Importantly, <strong>4q</strong> maintained potent inhibitory activity <em>in vivo</em>, achieving a tumor growth inhibition rate of 56.7 %, consistent with its robust <em>in vitro</em> efficacy. Molecular docking simulations further elucidated <strong>4q</strong>′s binding mode with Aurora kinase, providing a structural basis for its activity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118548"},"PeriodicalIF":5.9,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1016/j.ejmech.2025.118542
Dongping Yao , Ni Zhang , Qian Yao , Yongmei Xie , Rong Tian , Xiaoai Wu , Weihong Kuang
Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-a]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound 28, which showed high affinity with tau aggregates (Ki = 0.99 nM). Compound 28 also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct SNAr radiofluorination, 18F-28 was successfully produced with high radiochemical yield. In vitro stability tests and log D7.4 measurement indicated 18F-28 hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and in vivo PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with 18F-28 in normal mice and P301L transgenic mice, as well as a fast clearance from brain. 18F-28 was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of 18F-28 with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound 28 holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.
{"title":"Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations","authors":"Dongping Yao , Ni Zhang , Qian Yao , Yongmei Xie , Rong Tian , Xiaoai Wu , Weihong Kuang","doi":"10.1016/j.ejmech.2025.118542","DOIUrl":"10.1016/j.ejmech.2025.118542","url":null,"abstract":"<div><div>Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-<em>a</em>]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound <strong>28</strong>, which showed high affinity with tau aggregates (<em>K</em><sub><em>i</em></sub> = 0.99 nM). Compound <strong>28</strong> also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct S<sub>N</sub>Ar radiofluorination, <sup>18</sup>F-<strong>28</strong> was successfully produced with high radiochemical yield. <em>In vitro</em> stability tests and log <em>D</em><sub><em>7.4</em></sub> measurement indicated <sup>18</sup>F-<strong>28</strong> hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and <em>in vivo</em> PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with <sup>18</sup>F-<strong>28</strong> in normal mice and P301L transgenic mice, as well as a fast clearance from brain. <sup>18</sup>F-<strong>28</strong> was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of <sup>18</sup>F-<strong>28</strong> with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound <strong>28</strong> holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118542"},"PeriodicalIF":5.9,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.ejmech.2025.118553
Siyi Li , Yulu Wu , Wang Chen , Peng Zhu , Xin Lu , Jiaming Li , Xiaodong Ma , Xueyang Jiang
Ischemic stroke (IS) is an acute cerebrovascular condition marked by a high incidence, disability rate, and mortality. Edaravone and Dexborneol Concentrated Injection Solution (EDB) has been approved to improve neurological symptoms, daily living activities, and functional impairments resulting from acute IS. Our previous studies showed that replacing the benzene ring of Edaravone (Eda) with pyridine enhances its free radical scavenging capacity. In this study, we further oxidized the methyl group of Eda to a carboxylic acid and used a structural hybridization strategy with (+)-borneol to synthesize a series of pyrazole carboxylic acid borneol esters. We evaluated the free radical scavenging ability of the synthesized compounds, identifying candidate compound B16, which outperforms Eda. The IC50 values of B16 against DPPH and ABTS free radicals were 7.98 μM and 5.50 μM, respectively. Cellular studies have shown that B16 maintains intracellular redox homeostasis and mitochondrial function, while also alleviating DNA damage in an oxygen - glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell model, demonstrating excellent neuroprotective effects. Further in vivo pharmacodynamic studies have demonstrated that B16 not only restores cerebral blood flow and significantly reduces infarct size in middle cerebral artery occlusion/reperfusion (MCAO/R) mice, but also improves sensory and motor functions, and promotes the recovery of neuronal cells and the blood-brain barrier (BBB) in the brain. Notably, B16 exhibits excellent BBB permeability and shows promising brain exposure levels within 5 min of administration. Preliminary biosafety studies indicated no obvious organ toxicity from B16. Collectively, the pyrazole carboxylic acid borneol ester compound B16 holds promise as a candidate for anti-IS treatment.
{"title":"Pyrazole carboxylic acid borneol esters: Novel neuroprotective agents with rapid, efficient brain penetration for the treatment of ischemic stroke","authors":"Siyi Li , Yulu Wu , Wang Chen , Peng Zhu , Xin Lu , Jiaming Li , Xiaodong Ma , Xueyang Jiang","doi":"10.1016/j.ejmech.2025.118553","DOIUrl":"10.1016/j.ejmech.2025.118553","url":null,"abstract":"<div><div>Ischemic stroke (IS) is an acute cerebrovascular condition marked by a high incidence, disability rate, and mortality. <em>Edaravone and Dexborneol Concentrated Injection Solution</em> (EDB) has been approved to improve neurological symptoms, daily living activities, and functional impairments resulting from acute IS. Our previous studies showed that replacing the benzene ring of Edaravone (Eda) with pyridine enhances its free radical scavenging capacity. In this study, we further oxidized the methyl group of Eda to a carboxylic acid and used a structural hybridization strategy with (+)-borneol to synthesize a series of pyrazole carboxylic acid borneol esters. We evaluated the free radical scavenging ability of the synthesized compounds, identifying candidate compound <strong>B16</strong>, which outperforms Eda. The IC<sub>50</sub> values of <strong>B16</strong> against DPPH and ABTS free radicals were 7.98 μM and 5.50 μM, respectively. Cellular studies have shown that <strong>B16</strong> maintains intracellular redox homeostasis and mitochondrial function, while also alleviating DNA damage in an oxygen - glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell model, demonstrating excellent neuroprotective effects. Further in vivo pharmacodynamic studies have demonstrated that <strong>B16</strong> not only restores cerebral blood flow and significantly reduces infarct size in middle cerebral artery occlusion/reperfusion (MCAO/R) mice, but also improves sensory and motor functions, and promotes the recovery of neuronal cells and the blood-brain barrier (BBB) in the brain. Notably, <strong>B16</strong> exhibits excellent BBB permeability and shows promising brain exposure levels within 5 min of administration. Preliminary biosafety studies indicated no obvious organ toxicity from <strong>B16</strong>. Collectively, the pyrazole carboxylic acid borneol ester compound <strong>B16</strong> holds promise as a candidate for anti-IS treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118553"},"PeriodicalIF":5.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A series of pyrazole derivatives was designed, synthesized, and characterized spectroscopically. All the synthesized compounds were pharmacologically evaluated by in vitro and in vivo methods for their antidepressant activity. Amongst, VK16 and VK19 were the most potent inhibitors of the MAO-A enzyme with IC50 values of 0.06 ± 0.017 μM and 0.09 ± 0.019 μM, respectively, showing comparable efficacy to that of the reference standards. Additionally, these compounds were tested for their reversibility potential and found to be reversible inhibitors of the MAO-A enzyme, as a 100-fold dilution with the substrate solution restored over 68 % enzymatic activity. The in vivo FST and TST results corroborated well with the findings from in vitro MAO inhibition. Further, antioxidant properties were assessed using in vitro assays and the compounds were computationally analyzed through molecular docking, MD simulation, and DFT studies (in silico). The molecular docking results revealed that the compounds showed stronger interactions with key amino acid residues and better docking scores than the studied standard drugs. All selected compounds demonstrated favorable ADME properties, including good blood–brain barrier penetration and gastrointestinal absorption. Molecular dynamics simulations and DFT studies also confirmed the stability of VK16 and VK19 within the MAO-A binding site. Overall, VK16 and VK19 are emerged as promising antidepressant candidates, warranting further investigation for clinical development.
{"title":"Synthesis, antidepressant evaluation and computational insights on substituted pyrazoles as selective MAO-A inhibitors","authors":"Diksha Choudhary , Rajwinder Kaur , Kailash Jangid , Vinod Kumar , Bhupinder Kumar , Thishana Singh , Amritpal Kaur , Shareen Singh , Manjinder Singh , Thakur Gurjeet Singh , Balakumar Chandrasekaran","doi":"10.1016/j.ejmech.2026.118556","DOIUrl":"10.1016/j.ejmech.2026.118556","url":null,"abstract":"<div><div>A series of pyrazole derivatives was designed, synthesized, and characterized spectroscopically. All the synthesized compounds were pharmacologically evaluated by <em>in vitro</em> and <em>in vivo</em> methods for their antidepressant activity. Amongst, VK16 and VK19 were the most potent inhibitors of the MAO-A enzyme with IC<sub>50</sub> values of 0.06 ± 0.017 μM and 0.09 ± 0.019 μM, respectively, showing comparable efficacy to that of the reference standards. Additionally, these compounds were tested for their reversibility potential and found to be reversible inhibitors of the MAO-A enzyme, as a 100-fold dilution with the substrate solution restored over 68 % enzymatic activity. The <em>in vivo</em> FST and TST results corroborated well with the findings from <em>in vitro</em> MAO inhibition. Further, antioxidant properties were assessed using <em>in vitro</em> assays and the compounds were computationally analyzed through molecular docking, MD simulation, and DFT studies (<em>in silico</em>). The molecular docking results revealed that the compounds showed stronger interactions with key amino acid residues and better docking scores than the studied standard drugs. All selected compounds demonstrated favorable ADME properties, including good blood–brain barrier penetration and gastrointestinal absorption. Molecular dynamics simulations and DFT studies also confirmed the stability of VK16 and VK19 within the MAO-A binding site. Overall, VK16 and VK19 are emerged as promising antidepressant candidates, warranting further investigation for clinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118556"},"PeriodicalIF":5.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.ejmech.2025.118541
Jian-Mei Gao , Huilong Xie , Zi-Qiang Wang , Yu Huang , Yifan Ouyang , Yan Su , Nan Chao , Wenbo Yan , Hui Yuan , Junxun Zhou , Mei-Mei Zhang , Jiaxin He , Zhou Hong , Jiunlong Yang , Yanru Fan , Chang-Cai Bai , Yu Zhang , Huang Zeng , Hao Yang
Tumor resistance to chemotherapy, driven in part by DNA repair mechanisms, presents a major obstacle in cancer treatment. DNA topoisomerase 1B (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) are key enzymes involved in DNA replication and repair, and their coordinated activity can contribute to tumor cell survival and resistance to TOP1-targeted agents. In this study, a novel series of phenanthridine derivatives was rationally designed, synthesized, and evaluated for their potential as dual inhibitors of TOP1 and TDP1. Several compounds exhibited potent inhibitory activity against both targets, with compound C13 identified as a lead candidate, displaying strong inhibition of TOP1 (++++) and effective inhibition of TDP1 (IC50 = 17.8 ± 1.3 μM). In vitro, C13 showed notable antiproliferative effects against multiple cancer cell lines, particularly A549 cells (IC50 = 0.89 ± 0.25 μM), and induced apoptosis and suppressed clonogenic growth in a dose-dependent manner. Mechanistic studies revealed that C13 disrupts DNA repair pathways, and its combination with topotecan resulted in synergistic antitumor efficacy. Molecular dynamics simulations confirmed stable binding between C13 and both targets, while in vivo studies demonstrated low acute toxicity, favorable pharmacokinetic parameters, and pronounced tumor suppression. These findings highlight the promise of dual TOP1/TDP1 inhibition for overcoming tumor drug resistance and support the further development of C13 as a potential anticancer agent.
{"title":"Synthesis and biological evaluation of phenanthridine derivatives as dual-target inhibitors of DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), and potential antitumor agents","authors":"Jian-Mei Gao , Huilong Xie , Zi-Qiang Wang , Yu Huang , Yifan Ouyang , Yan Su , Nan Chao , Wenbo Yan , Hui Yuan , Junxun Zhou , Mei-Mei Zhang , Jiaxin He , Zhou Hong , Jiunlong Yang , Yanru Fan , Chang-Cai Bai , Yu Zhang , Huang Zeng , Hao Yang","doi":"10.1016/j.ejmech.2025.118541","DOIUrl":"10.1016/j.ejmech.2025.118541","url":null,"abstract":"<div><div>Tumor resistance to chemotherapy, driven in part by DNA repair mechanisms, presents a major obstacle in cancer treatment. DNA topoisomerase 1B (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) are key enzymes involved in DNA replication and repair, and their coordinated activity can contribute to tumor cell survival and resistance to TOP1-targeted agents. In this study, a novel series of phenanthridine derivatives was rationally designed, synthesized, and evaluated for their potential as dual inhibitors of TOP1 and TDP1. Several compounds exhibited potent inhibitory activity against both targets, with compound <strong>C13</strong> identified as a lead candidate, displaying strong inhibition of TOP1 (++++) and effective inhibition of TDP1 (IC<sub>50</sub> = 17.8 ± 1.3 μM). In vitro, <strong>C13</strong> showed notable antiproliferative effects against multiple cancer cell lines, particularly A549 cells (IC<sub>50</sub> = 0.89 ± 0.25 μM), and induced apoptosis and suppressed clonogenic growth in a dose-dependent manner. Mechanistic studies revealed that <strong>C13</strong> disrupts DNA repair pathways, and its combination with topotecan resulted in synergistic antitumor efficacy. Molecular dynamics simulations confirmed stable binding between <strong>C13</strong> and both targets, while in vivo studies demonstrated low acute toxicity, favorable pharmacokinetic parameters, and pronounced tumor suppression. These findings highlight the promise of dual TOP1/TDP1 inhibition for overcoming tumor drug resistance and support the further development of <strong>C13</strong> as a potential anticancer agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118541"},"PeriodicalIF":5.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.ejmech.2025.118534
Xiaodi Zhang , Shichao Zhang , Shuyuan Wu , Biao Xu , Jiamin Feng , Xuanran Hu , Ning Li , Nan Zhang , Mengna Zhang , Quan Fang
Recently, κ-opioid receptor (KOR) agonists have been attractive therapeutic candidates for the treatment of pain and pruritus. To advance the development of effective and safer peripherally restricted KOR agonists, we designed, synthesized, and evaluated 21 novel chimeric peptides incorporating the N-terminal tetrapeptide sequence of CR845 and the C-terminal “address” domain derived from dynorphin A. In vitro calcium mobilization assays confirmed the selective and full KOR agonism for all the compounds. Among these, analogues 4, 9, and 17 emerged as optimized analogues, exhibiting potent analgesic and antipruritic effects comparable to those of CR845 after subcutaneous administration, through the activation of the peripheral KOR. Additionally, subcutaneous administration of these 3 optimized analogues induced sedation without eliciting aversion or depressive-like side effects. Notably, analogue 4 was selected as the final candidate due to its high potency in KOR agonism and minimal sedative effects, making it the most promising drug candidate for the development of efficient and safe antinociceptive and antipruritic therapies.
{"title":"Rational design, synthesis and characterization of novel chimeric peptides containing the kappa-opioid agonists CR845 and dynorphin A-derived peptides","authors":"Xiaodi Zhang , Shichao Zhang , Shuyuan Wu , Biao Xu , Jiamin Feng , Xuanran Hu , Ning Li , Nan Zhang , Mengna Zhang , Quan Fang","doi":"10.1016/j.ejmech.2025.118534","DOIUrl":"10.1016/j.ejmech.2025.118534","url":null,"abstract":"<div><div>Recently, κ-opioid receptor (KOR) agonists have been attractive therapeutic candidates for the treatment of pain and pruritus. To advance the development of effective and safer peripherally restricted KOR agonists, we designed, synthesized, and evaluated 21 novel chimeric peptides incorporating the N-terminal tetrapeptide sequence of CR845 and the C-terminal “address” domain derived from dynorphin A. <em>In vitro</em> calcium mobilization assays confirmed the selective and full KOR agonism for all the compounds. Among these, analogues <strong>4</strong>, <strong>9</strong>, and <strong>17</strong> emerged as optimized analogues, exhibiting potent analgesic and antipruritic effects comparable to those of CR845 after subcutaneous administration, through the activation of the peripheral KOR. Additionally, subcutaneous administration of these 3 optimized analogues induced sedation without eliciting aversion or depressive-like side effects. Notably, analogue <strong>4</strong> was selected as the final candidate due to its high potency in KOR agonism and minimal sedative effects, making it the most promising drug candidate for the development of efficient and safe antinociceptive and antipruritic therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118534"},"PeriodicalIF":5.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ulcerative colitis (UC) is a chronic idiopathic enteritis, seriously affecting patients’ quality of life and significantly increasing the risk of cancer. We screened a marine natural product-derived library and identified a derivative (a4) of natural terphenyllin (1) as the bioactive scaffold for anti-inflammatory activity. To improve its activity, a total of 101 derivatives (a1–a29, b1–b40, and c1–c32) of a4 were rationally designed and semisynthesized. Among them, c13 (CHNQD-03005) emerged as the optimal lead, displaying the most potent inhibitory efficacy on the production of TNF-α, IL-6, and IL-1β with IC50 values ranging from 0.095 μM to 0.45 μM. Notably, c13 (1 mg/kg, p.o.) demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, together with a favorable safety profile (MTD >100 mg/kg, p.o.). Mechanistically, c13 alleviated colitis by suppressing the expression of inflammatory signaling iNOS/COX-2, and downregulating the levels of NO, TNF-α, IL-6, and IL-1β. In conclusion, this study provided a promising oral natural terphenyllin derivative c13, which inhibited multiple inflammatory pathways to impede colitis progression, as a therapeutic candidate in the treatment of UC for further development.
{"title":"Design, semisynthesis, and anti-inflammatory activity evaluation of a terphenyllin compound library for alleviating ulcerative colitis","authors":"Cui-Fang Wang , Tian-Yi Zhou , Liu-Xia Lv , Xi-Zhen Cao , Jun-Na Yin , Wen-Hui Wang , Qian-Qian Jing , Yu-Cheng Gu , Mei-Yan Wei , Guang-Ying Chen , Chang-Lun Shao","doi":"10.1016/j.ejmech.2025.118539","DOIUrl":"10.1016/j.ejmech.2025.118539","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic idiopathic enteritis, seriously affecting patients’ quality of life and significantly increasing the risk of cancer. We screened a marine natural product-derived library and identified a derivative (<strong>a4</strong>) of natural terphenyllin (<strong>1</strong>) as the bioactive scaffold for anti-inflammatory activity. To improve its activity, a total of 101 derivatives (<strong>a1</strong>–<strong>a29</strong>, <strong>b1</strong>–<strong>b40,</strong> and <strong>c1</strong>–<strong>c32</strong>) of <strong>a4</strong> were rationally designed and semisynthesized. Among them, <strong>c13</strong> (CHNQD-03005) emerged as the optimal lead, displaying the most potent inhibitory efficacy on the production of TNF-<em>α</em>, IL-6, and IL-1<em>β</em> with IC<sub>50</sub> values ranging from 0.095 μM to 0.45 μM. Notably, <strong>c13</strong> (1 mg/kg, p.o.) demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, together with a favorable safety profile (MTD >100 mg/kg, p.o.). Mechanistically, <strong>c13</strong> alleviated colitis by suppressing the expression of inflammatory signaling iNOS/COX-2, and downregulating the levels of NO, TNF-<em>α</em>, IL-6, and IL-1<em>β</em>. In conclusion, this study provided a promising oral natural terphenyllin derivative <strong>c13</strong>, which inhibited multiple inflammatory pathways to impede colitis progression, as a therapeutic candidate in the treatment of UC for further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118539"},"PeriodicalIF":5.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.ejmech.2025.118533
Lele Yi , Yifan Ping , Xiaolong Ye , Shaoli Wang , Yao Wu , Lingling Zhou , Xiangrui Song , Haojin Chen , Bin Li , Yixin Mao , Yang Chen , Zhihao Yu , Weiwei Xue , Jing Wang , Shengbin Huang , Zengqiang Song
The osteoclast is the only bone cell responsible for bone resorption, intracellular reactive oxygen species (ROS) are key signaling factors that regulate RANKL-induced osteoclast differentiation. Organoselenium compounds have been demonstrated with good antioxidant activity by scavenging ROS. However, these compounds exerting anti-osteoclastogenesis activity by reducing ROS levels have not been reported. In this study, a series of selenyl quinolinamides were synthesized using a novel, simple, and metal-free method at room temperature, and their osteoclastogenesis inhibitory effects in vitro were tested. The most promising compound 3w with an IC50 value of 0.577 μM, markedly inhibited RANKL-induced osteoclast formation, bone resorption, and osteoclast-specific genes and proteins expressions in vitro. Additionally, 3w suppressed RANKL-stimulated intracellular ROS levels by inhibition of ROS production and promotion of ROS scavenging, and inhibited downstream MAPK and NF-κB signaling pathways. In vivo, 3w significantly prevented bone loss in ovariectomized osteoporosis mice. Moreover, 3w could bind to RANKL and interfere with RANKL-RANK interaction. Our findings may offer a valuable direction for the development of novel organoselenium-based antiosteoporosis agents.
{"title":"A novel RANKL-targeted selenyl quinolinamide alleviates ovariectomy-induced bone loss through inhibiting ROS, MAPK and NF-κB signaling pathways","authors":"Lele Yi , Yifan Ping , Xiaolong Ye , Shaoli Wang , Yao Wu , Lingling Zhou , Xiangrui Song , Haojin Chen , Bin Li , Yixin Mao , Yang Chen , Zhihao Yu , Weiwei Xue , Jing Wang , Shengbin Huang , Zengqiang Song","doi":"10.1016/j.ejmech.2025.118533","DOIUrl":"10.1016/j.ejmech.2025.118533","url":null,"abstract":"<div><div>The osteoclast is the only bone cell responsible for bone resorption, intracellular reactive oxygen species (ROS) are key signaling factors that regulate RANKL-induced osteoclast differentiation. Organoselenium compounds have been demonstrated with good antioxidant activity by scavenging ROS. However, these compounds exerting anti-osteoclastogenesis activity by reducing ROS levels have not been reported. In this study, a series of selenyl quinolinamides were synthesized using a novel, simple, and metal-free method at room temperature, and their osteoclastogenesis inhibitory effects <em>in vitro</em> were tested. The most promising compound <strong>3w</strong> with an <em>IC</em><sub>50</sub> value of 0.577 μM, markedly inhibited RANKL-induced osteoclast formation, bone resorption, and osteoclast-specific genes and proteins expressions <em>in vitro</em>. Additionally, <strong>3w</strong> suppressed RANKL-stimulated intracellular ROS levels by inhibition of ROS production and promotion of ROS scavenging, and inhibited downstream MAPK and NF-κB signaling pathways. <em>In vivo</em>, <strong>3w</strong> significantly prevented bone loss in ovariectomized osteoporosis mice. Moreover, <strong>3w</strong> could bind to RANKL and interfere with RANKL-RANK interaction. Our findings may offer a valuable direction for the development of novel organoselenium-based antiosteoporosis agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118533"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-31DOI: 10.1016/j.ejmech.2025.118550
Huabin Hu , James Bowers , Justin Shumate , Louis Scampavia , Timothy P. Spicer , Xiangyan Yi , Albert A. Antolin , Jonathan B. Baell
The discovery of new therapeutics typically begins with screening compound collections against specific disease targets to identify bioactive small molecules. However, subsequent optimization is both time-consuming and costly, leading researchers to search for desired bioactivity in already-approved drugs with the hope of accelerating clinical development – a strategy often termed drug repurposing. While this strategy may seem beneficial, it carries significant risks, in particular with respect to lack of intellectual property control required to navigate regulatory pathways to the clinic. In this study, we have identified the more concerning phenomenon that widely used drug repurposing libraries are disproportionately populated by promiscuous compounds. Researchers lacking adequate medicinal chemistry expertise may overlook the spurious behaviors linked to certain molecular scaffolds, which can result in the advancement of misleading compounds into clinical trials. This misstep not only wastes scientific and financial resources but also could pose serious risks to patient safety by potentially enrolling them in ineffective trials. We call upon the biomedical community to implement rigorous validation processes for screening hits and to systematically exclude problematic compounds from drug repurposing libraries, thereby increasing the translational rate of future drug repurposing initiatives.
{"title":"Promiscuously bioactive compounds are prevalent in widely used commercial drug repurposing libraries","authors":"Huabin Hu , James Bowers , Justin Shumate , Louis Scampavia , Timothy P. Spicer , Xiangyan Yi , Albert A. Antolin , Jonathan B. Baell","doi":"10.1016/j.ejmech.2025.118550","DOIUrl":"10.1016/j.ejmech.2025.118550","url":null,"abstract":"<div><div>The discovery of new therapeutics typically begins with screening compound collections against specific disease targets to identify bioactive small molecules. However, subsequent optimization is both time-consuming and costly, leading researchers to search for desired bioactivity in already-approved drugs with the hope of accelerating clinical development – a strategy often termed drug repurposing. While this strategy may seem beneficial, it carries significant risks, in particular with respect to lack of intellectual property control required to navigate regulatory pathways to the clinic. In this study, we have identified the more concerning phenomenon that widely used drug repurposing libraries are disproportionately populated by promiscuous compounds. Researchers lacking adequate medicinal chemistry expertise may overlook the spurious behaviors linked to certain molecular scaffolds, which can result in the advancement of misleading compounds into clinical trials. This misstep not only wastes scientific and financial resources but also could pose serious risks to patient safety by potentially enrolling them in ineffective trials. We call upon the biomedical community to implement rigorous validation processes for screening hits and to systematically exclude problematic compounds from drug repurposing libraries, thereby increasing the translational rate of future drug repurposing initiatives.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118550"},"PeriodicalIF":5.9,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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