European Journal of Medicinal Chemistry最新文献

{"title":"Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation","authors":"Marine Michon ,&nbsp;Sebastien Curpanen ,&nbsp;Ombeline Pessey ,&nbsp;Robert Thai ,&nbsp;Jean-Charles Gaillard ,&nbsp;Gaëtan Herbette ,&nbsp;Karen Hinsinger ,&nbsp;Daniel Gillet ,&nbsp;Jean Armengaud ,&nbsp;Jean-Christophe Cintrat ,&nbsp;Julien Barbier","doi":"10.1016/j.ejmech.2026.118645","DOIUrl":"10.1016/j.ejmech.2026.118645","url":null,"abstract":"<div><div>PROteolysis TArgeting Chimeras are attracting growing interest in pharmaceutical research thanks to their catalytic and irreversible mechanism, which is capable of targeting proteins previously considered \"undruggable\". These bifunctional molecules hijack the cellular ubiquitin-proteasome system by recruiting E3 ligases (such as CRBN or VHL) to induce the selective degradation of a target protein. Their efficacy has been demonstrated against various disorders and several compounds have reached phase I-III clinical trials, reinforcing their appeal. In the fight against toxins, derivatives of the Retro-2 molecule (active against Shigatoxins, ricin, and various pathogens) have been developed. These molecules act on host cells by disrupting the intracellular trafficking of pathogens, targeting in particular the Sec16A and/or ASNA1 proteins. Our study presents the synthesis and characterization of new chemical probes based on PROTAC technology, combining a CRBN ligand derived from thalidomide, a Retro-2 derivative, and variable-length PEG chain linkers to better understand the mechanism of action of Retro-2-derived molecules. Contrary to initial assumptions, our results do not show proteasome-dependent degradation of the protein targets, but demonstrate that PEG-2 molecules can degrade the translation termination factor GSPT1 despite the normally propitious anchoring of the PEG linker at position 4 of the phthalimide ring. Furthermore, this study shows for the first time that GSPT1 degradation depends on the length of the flexible PEG chain linker.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118645"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116103","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}

{"title":"Synthesis of potent human DHRS11 inhibitors and their efficacy against androgen-dependent proliferation and sensitivity to AKT inhibitor Capivasertib of triple-negative breast cancer cells","authors":"Yuri Miyamoto ,&nbsp;Wakana Hirai ,&nbsp;Tomofumi Saka ,&nbsp;Masatoshi Tanio ,&nbsp;Yudai Kudo ,&nbsp;Yuta Yoshino ,&nbsp;Yusuke Nakagawa ,&nbsp;Nao Kobayashi ,&nbsp;Sana Takada ,&nbsp;Takuya Okada ,&nbsp;Naoki Toyooka ,&nbsp;Mahmoud Kandeel ,&nbsp;Nobutada Tanaka ,&nbsp;Akira Ikari ,&nbsp;Satoshi Endo","doi":"10.1016/j.ejmech.2026.118649","DOIUrl":"10.1016/j.ejmech.2026.118649","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Among its heterogeneous subtypes, luminal androgen receptor-positive (LAR) TNBC is driven by androgen signaling and presents limited treatment options. We previously identified dehydrogenase/reductase SDR family member 11 (DHRS11) as a novel enzyme involved in androgen biosynthesis, and demonstrated that Kobochromone A (<strong>KC-A</strong>), a polyphenol isolated from <em>Carex kobomugi</em>, inhibited androgen-driven proliferation in LAR TNBC cells via DHRS11 inhibition and AR downregulation.</div><div>In this study, we synthesized 23 structural derivatives of <strong>KC-A</strong> and identified <strong>WH23</strong> as the most potent DHRS11 inhibitor (IC₅₀ = 37 nM). Molecular docking and MM-PBSA analysis revealed that the 2′-hydroxy group of <strong>WH23</strong> forms a hydrogen bond with His210 of DHRS11, which was validated by site-directed mutagenesis. <strong>WH23</strong> suppressed AR mRNA and protein expression, reduced 11-ketodihydrotestosterone (11KDHT)-induced c-Myc expression, and inhibited proliferation of MDA-MB-453 cells. Additionally, <strong>WH23</strong> inhibited PI3K/AKT signaling, reducing phosphorylation of PDK1, AKT, mTOR, and ERK. Capivasertib (<strong>Cap</strong>), a clinically approved pan-AKT inhibitor, induced DHRS11 expression in MDA-MB-453 cells. Although <strong>Cap</strong> and <strong>WH23</strong> did not show synergistic cytotoxicity in parental cells, <strong>Cap</strong>-resistant (Cap-R) cells, which exhibited elevated DHRS11 and c-Myc expression, showed significant sensitivity to the combination. In Cap-R cells, the combination of <strong>Cap</strong> and <strong>WH23</strong> significantly induced apoptosis, demonstrating a synergistic anticancer effect.</div><div>These findings establish WH23 as a dual-acting compound targeting both androgen biosynthesis and AR signaling, with potential to overcome AKT inhibitor resistance in LAR TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118649"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122318","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}

{"title":"Marine natural product-inspired 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3H)-one derivative CHNQD-01522: A novel anti-hepatocellular carcinoma agent targeting colchicine binding site of microtubule","authors":"Peng-Jie Li ,&nbsp;Chao-Jie Wang ,&nbsp;Rui-Qin Zhai ,&nbsp;Ji-Xiu Gao ,&nbsp;Hao-Ran Li ,&nbsp;Jian-Yu Liu ,&nbsp;Mei-Yan Wei ,&nbsp;Yu-Cheng Gu ,&nbsp;Chang-Lun Shao","doi":"10.1016/j.ejmech.2026.118658","DOIUrl":"10.1016/j.ejmech.2026.118658","url":null,"abstract":"<div><div>Microtubule targeting agents are effective in cancer therapy, but current inhibitors face challenges including systemic toxicity and P-glycoprotein (P-gp) mediated drug resistance, underscoring the need for novel microtubule inhibitors. Quinazolin-4(3<em>H</em>)-one alkaloids, with diverse targets, exhibit significant potential for developing novel anti-cancer agents. Herein, inspired by marine quinazolin-4(3<em>H</em>)-one alkaloid penipanoid C, compounds <strong>1‒55</strong>, a series of 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3<em>H</em>)-one derivatives were synthesized and identified. Among them, CHNQD-01522 (<strong>18</strong>) exhibited the strongest cytotoxic activity against Huh-7 and HepG2 cell lines with IC₅₀ values of 0.19 and 0.17 μM. Meanwhile, treatment with CHNQD-01522 (<strong>18</strong>) suppressed tumor cell colony formation, arrested cell cycle in G2/M phases, and induced apoptosis. Mechanistic studies revealed that it is a novel microtubule inhibitor targeting the colchicine binding site, which cannot be transported by P-gp in cancer cells. Encouragingly, CHNQD-01522 (<strong>18</strong>) showed significant <em>in vivo</em> anti-tumor efficacy in the subcutaneous xenograft tumor model (TID, TGI = 79.09%) with frequency dependence. More importantly, the anti-tumor efficacy was also verified in an orthotopic xenograft tumor model. Furthermore, CHNQD-01522 (<strong>18</strong>) displayed satisfactory safety profiles in preliminary toxicity studies. Taken together, this study has identified a novel microtubule inhibitor with significant anti-hepatocellular carcinoma (HCC) activity, inherent resistance-avoidance property, and a favorable safety profile, showing promise as an HCC therapeutic.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118658"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135330","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}

{"title":"Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma","authors":"Jing Ye ,&nbsp;Daihan Wang ,&nbsp;Haiying Pang ,&nbsp;Qiao Liu ,&nbsp;Zhaoping Pan ,&nbsp;Lian Wang ,&nbsp;Bo Liu ,&nbsp;Gu He","doi":"10.1016/j.ejmech.2026.118633","DOIUrl":"10.1016/j.ejmech.2026.118633","url":null,"abstract":"<div><div>Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is an essential regulator in the initiation of autophagy and represents a novel therapeutic target for colorectal cancer (CRC) treatment. Herein, we developed a series of novel ULK1 covalent inhibitors through structure-based and medicinal chemistry optimizations. Notably, compound <strong>12i</strong> was synthesized and validated to form covalent bonds with ULK1, exhibiting pronounced selectivity and potent inhibitory activity (ULK1 IC₅₀ = 4.7 μM). Moreover, <strong>12i</strong> demonstrated anti-proliferative effects in CRC cell lines. <em>In vitro</em> experiments showed that <strong>12i</strong> effectively inhibited CRC cell growth, induced cell cycle arrest at the S or G2/M phase, and triggered apoptosis by blocking ULK1-mediated autophagy. Additionally, <em>in vivo</em> results showed that <strong>12i</strong> also exhibited good tumor inhibitory activity in CRC murine models, with an inhibition rate of 70.4 % at 40 mg/kg. <em>In vivo</em> pharmacokinetic studies revealed moderate systemic absorption (T_max = 2 h) with oral bioavailability of 39.7 % in rats. In summary, our findings highlight compound <strong>12i</strong> as a promising lead candidate for further development of selective ULK1 covalent inhibitors, offering a potential new strategy for CRC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118633"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095638","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}

{"title":"Design and synthesis of novel triazole-metronidazole boswellic acid hybrids for ovarian cancer targeting","authors":"Sadiq Noor Khan ,&nbsp;Samira Farhadi ,&nbsp;Najeeb Ur Rehman ,&nbsp;Sobia Ahsan Halim ,&nbsp;Issa S. Al-Amri ,&nbsp;Ajmal Khan ,&nbsp;Muhammad U. Anwar ,&nbsp;René Csuk ,&nbsp;Satya Kumar Avula ,&nbsp;Ahmed Al-Harrasi","doi":"10.1016/j.ejmech.2026.118653","DOIUrl":"10.1016/j.ejmech.2026.118653","url":null,"abstract":"<div><div>In this study, we report the design, synthesis, and biological evaluation of a new series of triterpenoid metronidazole-linked 1<em>H</em>-1,2,3-triazole conjugates (<strong>16</strong>–<strong>23</strong>) as potential targeted therapies. These compounds were screened across a panel of ovarian cancer cell lines. The cytotoxic profiles of all <em>β</em>-AKBA and <em>β</em>-ABA metronidazole–triazole hybrids were evaluated against normal endothelial cells (HUVEC), cisplatin-sensitive ovarian cancer cells (A2780-S), and cisplatin-resistant cells (A2780-CP). Several derivatives showed enhanced cytotoxicity relative to their parent triterpenoids, with compound <strong>21</strong> exhibiting the most favourable selectivity index (SI ≈ 1.61), demonstrating preferential toxicity toward malignant cells while sparing normal cells. The selective cytotoxicity is controlled by reaching an ideal balance of molecular weight, topological polar surface area, hydrogen-bonding characteristics, and nitrogen-rich substituents, according to structure-activity relationship (SAR) studies. Computational docking studies further confirmed that compound <strong>21</strong> displays strong complementarity and robust binding affinity toward PARP6, suggesting a possible mechanism of action through PARP6 modulation. The study provides a promising platform for advancing triterpenoid-based targeted therapeutics in ovarian cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118653"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135343","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}

{"title":"A combination of salinomycin or its C20 triphenylphosphonium-conjugated derivative with carboplatin leads to autophagy in ovarian cancer cells – An in vitro study","authors":"Marcin Michalak ,&nbsp;Michał S. Lach ,&nbsp;Katarzyna Regulska ,&nbsp;Marta Jędrzejczyk ,&nbsp;Michał Antoszczak ,&nbsp;Monika A. Rosochowicz-Kamińska ,&nbsp;Błażej Nowakowski ,&nbsp;Wiktoria M. Suchorska ,&nbsp;Adam Huczyński","doi":"10.1016/j.ejmech.2026.118656","DOIUrl":"10.1016/j.ejmech.2026.118656","url":null,"abstract":"<div><div>Ovarian cancer (OvCa) remains a major therapeutic challenge due to limited treatment options and frequent late-stage diagnosis, which contribute to high recurrence rates and mortality. Advances in synthetic organic chemistry and the development of novel oncology-targeted molecules offer promising new directions. In this study, we aimed to evaluate salinomycin (<strong>SAL</strong>) and its semisynthetic derivatives as potential candidates for OvCa therapy. Among the synthesized C20 <strong>SAL</strong> derivatives, we selected compound <strong>8</strong>, featuring a triphenylphosphonium (TPP⁺) motif and exhibiting a cytotoxicity profile comparable to that of the parent molecule, for further investigation of its anticancer mechanism of action. In combination with carboplatin (CBP), we investigated the interactions and effects on cell viability, cell cycle distribution, reactive oxygen species (ROS) production, mitochondrial membrane potential, and autophagy markers. Our findings indicated that <strong>SAL</strong> and <strong>8</strong> share a similar mechanism of action, inducing G0/G1 cell cycle arrest, reducing ROS production, and disrupting mitochondrial integrity, thereby promoting autophagy rather than classical cell death pathways in the tested OvCa cell lines. These results suggest that the TPP⁺-conjugated <strong>SAL</strong> derivatives may be promising therapeutic candidates for the management of OvCa, either as monotherapy or in combination with CBP and related drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118656"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146596","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}

{"title":"Discovery of 9-arylamino-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline-8-carbonitriles: Potent inducers of immunogenic cell death via colchicine site-targeted microtubule polymerization inhibition","authors":"Yan Ma ,&nbsp;Zhangjian Han ,&nbsp;Youyou Feng ,&nbsp;Xiangyu Kong ,&nbsp;Yabo Wang ,&nbsp;Lin Li ,&nbsp;Wen Yang ,&nbsp;Kehao Yang ,&nbsp;Ting Zhang ,&nbsp;Zhuang Li ,&nbsp;Han Wen ,&nbsp;Shuaijia Liu ,&nbsp;Yanbo Zheng ,&nbsp;Wenjie Guo ,&nbsp;Weiwei Niu ,&nbsp;Yifan Liu ,&nbsp;Kai Zhang","doi":"10.1016/j.ejmech.2026.118618","DOIUrl":"10.1016/j.ejmech.2026.118618","url":null,"abstract":"<div><div>A series of microtubule polymerization inhibitors that target the colchicine site on the basis of a new scaffold have been developed. Among them, compound <strong>17</strong> exhibited outstanding comprehensive antitumor efficacy against a panel of cancer cell lines (with an average IC₅₀ value of 17.7 nM). Paclitaxel resistance was successfully overcome in a xenograft model in which paclitaxel-resistant A549/TxR cells were used in BALB/c nude mice, as expected. Moreover, the outstanding antitumor efficacy of compound <strong>17</strong> is attributed not only to its chemical toxicity but also to its ability to induce immunogenic cell death (ICD). <em>In vitro</em>, compound <strong>17</strong> potently induced immunogenic cell death in A549 cells at 80 nM, outperforming the reference drug doxorubicin at 200 nM. In the C57BL/6 mouse LLC model, compound <strong>17</strong> achieved a remarkable 81.6% tumor growth inhibition rate and effectively promoted the infiltration of CD4⁺ and CD8⁺ T cells into the tumor microenvironment and increased the levels of multiple serum immune factors. These results highlight <strong>17</strong> as a promising candidate for the development of novel chemoimmunotherapy strategies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118618"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146688","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}

{"title":"Discovery of 3-indolealkylamines as novel dual-target σ1R/H3R ligands with potent analgesia","authors":"Xiong Chen ,&nbsp;Zong-Zheng Li ,&nbsp;Xing-Yu Yao,&nbsp;Xiao-Min Han,&nbsp;Kai-Le Zeng,&nbsp;Hao-Yun Chen,&nbsp;Wen-Jing Gao,&nbsp;Tian-Yue Zhu,&nbsp;Lei Niu,&nbsp;Tao Zhuang","doi":"10.1016/j.ejmech.2026.118616","DOIUrl":"10.1016/j.ejmech.2026.118616","url":null,"abstract":"<div><div>Dual-acting ligands targeting the sigma-1 receptor (σ₁R) and histamine H₃ receptor (H₃R) are emerging as promising candidates for novel and safe analgesics. In this work, we designed, synthesized, and evaluated twenty-nine 3-indolealkylamines as dual σ₁R/H₃R ligands. <em>In vitro</em> radioligand receptor binding assay or surface plasmon resonance assay were performed to determine their affinities toward σ₁R or H₃R. Among them, compound <strong>67</strong> demonstrated high binding affinity for both σ₁R (Kᵢ = 8.8 nM) and H₃R (K_D = 31.2 nM). Further <em>in vivo</em> pharmacological evaluations confirmed its antagonistic activity at both receptors. Compound <strong>67</strong> exhibited significant antinociceptive effects in the acetic acid-induced constriction test (ED₅₀ = 0.18 mg/kg) and paclitaxel-induced neuropathic pain model (ED₅₀ = 0.06 mg/kg), which demonstrated potency superior to that of marketed drug gabapentin. Moreover, compound <strong>67</strong> showed no side effects in the open-field test and rotarod test, and acute toxicity studies revealed a high safety profile with an excellent therapeutic window (LD₅₀ &gt; 250 mg/kg, TI &gt; 1388.9). These findings demonstrated that compound <strong>67</strong> is a promising dual σ₁R/H₃R ligand to develop safe and effective analgesics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118616"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033859","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}

{"title":"Small-molecule modulators of the necroptotic pathway: A medicinal chemistry perspective","authors":"De-Chang Li ,&nbsp;Nan-Nan Chen ,&nbsp;Qi-Dong You ,&nbsp;Xiao-Li Xu","doi":"10.1016/j.ejmech.2026.118623","DOIUrl":"10.1016/j.ejmech.2026.118623","url":null,"abstract":"<div><div>Necroptosis, a regulated form of programmed necrosis mediated by the RIPK1/RIPK3/MLKL signaling pathway, plays a pivotal role in the pathogenesis of diverse diseases, including neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, infections, and cancer. This review comprehensively summarizes the significant progress in developing small-molecule modulators targeting core components of the pathway. It systematically details the classification, mechanisms of action, and SAR of RIPK1, RIPK3, and MLKL inhibitors and inducers. Notably, Several RIPK1 inhibitors (e.g., DNL-788, DNL-758, R-552) have advanced to Phase II clinical trials for indications like multiple sclerosis, ulcerative colitis, and rheumatoid arthritis. Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118623"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071905","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}

{"title":"Construction and biological evaluation of novel carbazole-5-phenyl-1,3,4-oxadiazole derivatives as multi-target hypoglycemic agents","authors":"Shuang Luo ,&nbsp;Zhiyun Peng ,&nbsp;Guangcheng Wang","doi":"10.1016/j.ejmech.2026.118615","DOIUrl":"10.1016/j.ejmech.2026.118615","url":null,"abstract":"<div><div>To achieve new multi-target inhibitors simultaneously acting on α-glucosidase, α-amylase, and protein tyrosine phosphatase 1B (PTP1B), twenty-one novel carbazole-5-phenyl-1,3,4-oxadiazole derivatives (<strong>5a-5u</strong>) were synthesized and screened for <em>in vitro</em> enzyme inhibitory activity. All synthesized derivatives <strong>5a-5u</strong> showed noticeable anti-α-glucosidase and anti-α-amylase activities (IC₅₀: 9.79 ± 0.21–132.65 ± 1.52 μM, 6.15 ± 0.11–25.16 ± 0.75 μM, respectively) in comparison with the standard acarbose (IC₅₀: 210.57 ± 0.91 μM, 26.17 ± 1.12 μM, respectively). The compound <strong>5l</strong> that possessed the best inhibition activity on both α-glucosidase and α-amylase (IC₅₀ = 9.79 ± 0.21, 6.36 ± 0.16 μM, respectively) also exhibited a fine inhibitory effect on PTP1B with an IC₅₀ value of 19.08 ± 4.52 μM, as the reference drug ursolic acid of 4.43 ± 0.40 μM. Kinetic measurement, multispectral techniques, and molecular docking study were used to reveal the interaction mechanism of preferred compound <strong>5l</strong> with α-glucosidase, α-amylase, and PTP1B. The derivative <strong>5l</strong> could inhibit the activity of these enzyme proteins <em>via</em> binding to the enzyme or its substrate complex, quenching their intrinsic fluorescence, or affecting the conformation of enzyme proteins, and forming hydrophobic interactions and hydrogen bonds with them. In conjunction with the potential properties of compound <strong>5l</strong> in inhibiting the postprandial blood glucose rise and low cytotoxicity, the title derivatives are expected to become lead molecules in developing new multi-target antidiabetes drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118615"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043115","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}