European Journal of Medicinal Chemistry最新文献

{"title":"Discovery of novel ENPP1 inhibitors with benzotriazole core for cancer immunotherapy","authors":"Junghwan Choi ,&nbsp;Sunwoo Lee ,&nbsp;Yong-Yea Park ,&nbsp;Jihun Kim ,&nbsp;Haein Kim ,&nbsp;Kyeongwon Moon ,&nbsp;Sunyoung Park ,&nbsp;Eun Kyung Yoo ,&nbsp;Chang Won Min ,&nbsp;Hyouk Woo Lee ,&nbsp;Hyun-Ju Park ,&nbsp;Pargat Singh ,&nbsp;Sungjoon Kim ,&nbsp;Chan Sun Park ,&nbsp;In Su Kim","doi":"10.1016/j.ejmech.2026.118666","DOIUrl":"10.1016/j.ejmech.2026.118666","url":null,"abstract":"<div><div>The cGAS-STING signaling pathway is an essential mechanism in the recruitment and activation of innate and adaptive immune cells to exert an antitumor response in cancer immunotherapy. cGAMP is a crucial immunotransmitter, which is potentially degraded by ENPP1, resulting in the deactivation of STING-mediated antitumor immune responses. We herein describe the design, synthesis, and biological evaluation of novel ENPP1 inhibitors containing a benzotriazole core and a sulfonimidamide Zn binder. Notably, compound <strong>44a</strong> demonstrated potent and selective ENPP1 inhibition with an IC₅₀ value of 13.1 nM and effectively activated the STING pathway in HCT116-Dual™ cells. Additionally, compound <strong>44a</strong> exhibited a notable release of cytokines in THP-1 cell lines, thereby enhancing the innate immune response. The oral administration of compound <strong>44a</strong> displayed remarkable antitumor efficacy in the MC38 syngeneic mouse model without notable toxicity. Therefore, compound <strong>44a</strong> can be considered a promising candidate as a selective and orally bioavailable ENPP1 inhibitor.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118666"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153257","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":"Xanthine oxidase inhibitors for gout: Applications and novel drug development","authors":"Weiping Lyu ,&nbsp;Haoming Qin ,&nbsp;Xiaonan Zhou ,&nbsp;Yihan Zhang ,&nbsp;Dehua Lu ,&nbsp;Yongxiang Shao ,&nbsp;Yanming Chen ,&nbsp;Mingxiu Liang ,&nbsp;Qi Li ,&nbsp;Xiaowei Chi ,&nbsp;Liangren Zhang ,&nbsp;Cheng Shi ,&nbsp;Zhenming Liu","doi":"10.1016/j.ejmech.2026.118619","DOIUrl":"10.1016/j.ejmech.2026.118619","url":null,"abstract":"<div><div>Hyperuricemia is a well-established direct trigger of gouty arthritis. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid production, represents a core therapeutic target for gout. Although XO inhibitors like allopurinol and febuxostat are widely-used clinically, their limitations, including severe hypersensitivity and cardiovascular risks, necessitate the continuous pursuit of safer and more efficient agents. This review provides a systematic and critical assessment of recent advances in XO inhibitor research, proposing for the first time a unified classification framework based on the evolution of drug design strategies. We comprehensively cover diverse chemical entities, from structure-based, rationally designed compounds to natural products and their corresponding analogs, with a particular emphasis on cutting-edge strategies designed to overcome existing drawbacks. These include dual-target inhibitors (e.g., targeting XO/URAT1 or XO/NLRP3) and drug repurposing. By delving into the structure-activity relationships within each inhibitor class, we identify crucial pharmacophores and optimization principles. Finally, the review offers a forward-looking perspective, critically discussing current research challenges and outlining future directions, such as leveraging artificial intelligence and advanced computational simulations for lead optimization. This work is intended to serve as a clear theoretical blueprint and a practical source of inspiration for medicinal chemists designing the next generation of highly effective and low-toxicity anti-gout therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118619"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135339","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":"Structural optimization of AR and AR-V7 degraders incorporating silicon-based hydrophobic tags for treatment of castration-resistant prostate cancer","authors":"Lei Xu ,&nbsp;Mengmeng Wang ,&nbsp;Yanshuo Cheng ,&nbsp;Hanhan Kuang ,&nbsp;Yijing Zhu ,&nbsp;Ning Liu ,&nbsp;Qianqian Wang ,&nbsp;Shicong Li ,&nbsp;Jiefu Wang ,&nbsp;Junfeng Wang ,&nbsp;Ziqi Huang ,&nbsp;Ranlu Liu ,&nbsp;Shuangwei Liu ,&nbsp;Kun Zhang ,&nbsp;Guang Yang","doi":"10.1016/j.ejmech.2026.118617","DOIUrl":"10.1016/j.ejmech.2026.118617","url":null,"abstract":"<div><div>Androgen receptor splice variant 7 (AR-V7) plays a crucial role in the malignant progression of castration-resistant prostate cancer (CRPC). Current research has demonstrated that the development of novel AR-V7 degraders holds broad prospects and is expected to serve as a clinical therapeutic regimen for this disease. In the present work, we utilized structural analogs of enzalutamide to conjugate a silicon-containing hydrophobic tag (SiHyT) moiety via Click chemistry, achieving the selective degradation of the androgen receptor (AR) and AR-V7. Mechanistic studies revealed that the degrader disrupted the interactions between AR/AR-V7 and HSP90. This disruption further prompted the E3 ubiquitin ligase helicase-like transcription factor (HLTF) to recognize AR and AR-V7, followed by their ubiquitination and degradation in CRPC cell lines. Additionally, the active compound exhibited favorable pharmacokinetic properties and metabolic profiles. In both <em>in vitro</em> and <em>in vivo</em> experiments, this degrader displayed more potent activity than enzalutamide in inhibiting the proliferation and migration of CRPC cells. This study expands the application scope of the silicon-containing hydrophobic tag (SiHyT) strategy and provides an alternative design concept for the development of drugs targeting the degradation of AR/AR-V7 in the treatment of CRPC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118617"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095637","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":"New antitubercular pretomanid analogues as potent payloads in polymeric micelles: Leveraging zebrafish assays to accelerate lead optimisation","authors":"Andrew M. Thompson ,&nbsp;Nils-Jørgen K. Dal ,&nbsp;Francesca Boldrin ,&nbsp;Noelia Alonso-Rodriguez ,&nbsp;Gabriela Schäfer ,&nbsp;Kerstin Johann ,&nbsp;Martin Speth ,&nbsp;Laura Cioetto-Mazzabò ,&nbsp;Adrián Pál ,&nbsp;Jana Korduláková ,&nbsp;Matthias Barz ,&nbsp;Federico Fenaroli ,&nbsp;William A. Denny ,&nbsp;Gareth Griffiths","doi":"10.1016/j.ejmech.2026.118622","DOIUrl":"10.1016/j.ejmech.2026.118622","url":null,"abstract":"<div><div>Third-generation derivatives of the tuberculosis drug pretomanid featuring acetylene-bridged aryl-heteroaryl or heterotriaryl side chains were designed as novel agents for nanoparticle-based delivery, seeking better efficacy and safety. While all nitro compounds retained excellent activity against <em>Mycobacterium tuberculosis</em>, several examples in the latter class excelled as having potency superior to the original lead (<strong>7</strong>) but equivalent to or reduced lipophilicity, implying enhanced lipophilic efficiency. Initial studies suggested a similar mode of action against the related fish pathogen, <em>M. marinum</em>; therefore, fourteen candidates were further assessed as micellar formulations in <em>M. marinum-</em>infected zebrafish embryo assays. Overall, the best new analogue was <strong>14</strong> (the 6-amino-linked congener of <strong>7</strong>), which was non-toxic and displayed efficacy comparable to <strong>7</strong> in both the blood and neural tube <em>M. marinum</em> infection models. Lead <strong>14</strong> also exhibited high microsomal stability, moderate cell permeability in an MDR1-MDCKII screen, and an enhanced pharmacokinetic profile in mice, with 93 % oral bioavailability.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118622"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089516","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":"Advances in pyrimidine-like heterocyclic scaffolds: Innovative synthetic method for malic enzyme inhibition in pancreatic ductal adenocarcinoma (PDAC) - A comprehensive review","authors":"Shubham Mehta ,&nbsp;Iti Patel ,&nbsp;Gautam Patel","doi":"10.1016/j.ejmech.2026.118657","DOIUrl":"10.1016/j.ejmech.2026.118657","url":null,"abstract":"<div><div>Pancreatic cancer remains one of the most lethal cancers of the 21st century due to extensive metabolic reprogramming and a highly adaptable tumor microenvironment that fosters relentless growth and resistance to treatment. Molecular docking studies targeted on malic enzyme facilitate the discovery of possible inhibitors that interfere with pancreatic cancer metabolism. Understanding the molecular circuitry of this disease, especially through the use of heterocyclic frameworks that inhibit metabolic needs specific to cancer, has enabled targeted therapy. Pyrimidine and fused-pyrimidine structures have become unique scaffolds because they are very good at breaking down metabolic checkpoints that are important for tumors to stay alive. Pyrimidine derivatives are at the forefront of developing next-generation anticancer drugs because they inhibit the malic enzyme (ME), which is a key regulator of redox homeostasis and biosynthetic flux in pancreatic cancers. This review gives a full picture of the synthetic methods that make it easy to quickly change the structure of pyrimidine-based pharmacophores. Some of these strategies are old, like Vorbrüggen glycosylation and HATU-mediated peptide coupling. Others are new, like chalcone-guanidine cyclocondensation and modular multi-component protocols. Pyrimidine scaffolds are crucial elements of precision oncology, evidenced by data from preclinical and clinical studies that underscore the therapeutic translatability of targeting metabolic abnormalities in pancreatic cancer. Even though chemotherapy, targeted therapy, and immunotherapy have all become better in the last few years, treating pancreatic cancer is still challenging due to its late diagnosis, the drug resistance, and the fact that there aren't many suitable options for treatment. Apart from that, there are still some big problems to solve, like metabolic redundancy, isoform-selective ME inhibition, and the tumor microenvironment, which makes treatment harder. To overcome these challenges, the amalgamation of multi-pathway inhibition, AI-driven lead optimization, and nanotechnology-facilitated targeted delivery offers considerable promise. This review emphasizes the crucial function of pyrimidine scaffolds in revolutionizing the therapeutic strategy for pancreatic cancer, linking mechanistic understanding to practical drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118657"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135332","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":"Rational design of dual PB2/JAK2 inhibitors achieving balanced antiviral and host-directed immunomodulatory effects","authors":"Yujian Yang ,&nbsp;Binhao Rong ,&nbsp;Huanyu Shi ,&nbsp;Kunyu Lu ,&nbsp;Xinxin Lin ,&nbsp;Yuanmei Wen ,&nbsp;Xingyu Zhou ,&nbsp;Peisen Zheng ,&nbsp;Xinshan Deng ,&nbsp;Xumu Zhang ,&nbsp;Shuwen Liu ,&nbsp;Qifan Zhou","doi":"10.1016/j.ejmech.2026.118642","DOIUrl":"10.1016/j.ejmech.2026.118642","url":null,"abstract":"<div><div>Infection with the influenza virus provokes an excessive immune reaction, triggering a cytokine storm that can cause severe inflammation and lead to conditions such as pneumonia and myocarditis. Herein, we propose a dual-target strategy that simultaneously targets the viral PB2 protein and the host JAK2 kinase, aiming to not only eliminate the virus but also modulate the immune response, facilitating rapid recovery of the body's health. In this article, the design and discovery of novel PB2/JAK2 dual-target inhibitors are reported. Through rational design and structure-guided optimization, we identified compound <strong>4B</strong>, which exhibited potent anti-H1N1 activity (MDCK cell EC₅₀ = 15 nM) and JAK2 inhibitory activity (JAK2 IC₅₀ = 49 nM). <strong>Notably, 4B demonstrated favorable pharmacokinetic properties in mice, achieving excellent oral bioavailability (F = 99.4%).</strong> Furthermore, our findings show that compound <strong>4B</strong> significantly downregulates NP and PB2 protein expression. Concurrently, <strong>4B</strong> also inhibits the mRNA expression of key pro-inflammatory cytokines (IL-6, TNF-α, IFN-β) in both inflammatory and influenza-infected models. This study demonstrates the promising potential of dual inhibition, targeting both viral replication and the host inflammatory response, for the development of anti-influenza therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118642"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135341","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 optimization of N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)amide derivatives as potent anti-inflammatory agents against LPS-induced acute lung injury","authors":"Zhe Wang ,&nbsp;Zhengtong Mao ,&nbsp;Chunwei Shen ,&nbsp;Renying Wang,&nbsp;Bin Liu,&nbsp;Xingxian Zhang","doi":"10.1016/j.ejmech.2026.118639","DOIUrl":"10.1016/j.ejmech.2026.118639","url":null,"abstract":"<div><div>Efficient treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) can be achieved by inhibiting the inflammatory cascade and reducing pulmonary inflammation. A series of novel <em>N</em>-(3-((4-(1<em>H</em>-indol-3-yl)pyrimidin-2-yl)amino)phenyl)amide derivatives were rationally designed and synthesized as cathepsin L (CTSL) inhibitors to reduce the expression of pro-inflammatory cytokines. Among these compounds, <strong>B5</strong> exhibited dose-dependent inhibition of pro-inflammatory cytokine production in HBE cells, with IC₅₀ values of 2.51 μM for IL-6 and 1.15 μM for IL-8, without inducing significant cytotoxicity <em>in vitro</em>. In addition, <strong>B5</strong> effectively inhibited CTSL enzymatic activity, with an IC₅₀ value of 5.52 μM. In LPS-induced ALI mouse model, treatment with <strong>B5</strong> (20 mg/kg) significantly reduced inflammatory cell infiltration into lung tissue, thereby markedly alleviating lung injury. Mechanistic studies revealed that <strong>B5</strong> suppresses CTSL maturation, which in turn attenuates activation of the downstream NF-κB and p38 MAPK signaling pathways. Molecular docking further demonstrated that <strong>B5</strong> establishes stable binding in the active site of CTSL through multiple noncovalent interactions with key residues Asp162, Cys25, and Glu63. Specifically, the NH linker, the pyrimidine ring, and the amino group participate in hydrogen bonding, π–sulfur interactions, and electrostatic interactions, respectively. These findings indicate that <strong>B5</strong> exhibits potent anti-inflammatory activity both <em>in vitro</em> and <em>in vivo</em> and represents a promising lead compound for the treatment of ALI.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118639"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109849","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":"Structural optimization of natural product honokiol to discover novel membrane-targeting antibacterial agents against Gram-positive bacteria","authors":"Ninan Dai ,&nbsp;Yiyu Wang ,&nbsp;Yong Yang ,&nbsp;Yuting Zhang ,&nbsp;Huan Ge ,&nbsp;Farhad Ghazali ,&nbsp;Bao Fu ,&nbsp;Yinhu Wang ,&nbsp;Song Qin","doi":"10.1016/j.ejmech.2026.118674","DOIUrl":"10.1016/j.ejmech.2026.118674","url":null,"abstract":"<div><div>The global increase in infections caused by multidrug-resistant bacteria, coupled with a dwindling antibiotic pipeline, underscores an urgent need for new therapeutic agents. Inspired by the design principles of cationic antimicrobial peptides, we developed a new class of honokiol-based amphiphiles. From this series, compound <strong>20C</strong> emerged as a promising lead, demonstrating potent <em>in vitro</em> activity against Gram-positive bacteria (MICs = 0.5-2 μg/mL). It exhibited a favorable safety profile characterized by low hemolytic (HC₅₀ = 771.8 μg/mL) and cytotoxic activity (CC₅₀ = 28.03 μg/mL), along with good plasma stability. <strong>20C</strong> also displayed rapid bactericidal kinetics, a low resistance frequency, and efficacy in inhibiting biofilm formation and disrupting mature biofilms. A detailed mechanistic investigation established that <strong>20C</strong> exerted its effect by dissipation of membrane potential, increasing permeability, thereby disrupting membrane integrity. This primary membrane damage triggered secondary lethal events, including ROS accumulation and leakage of proteins and DNA. Notably, <strong>20C</strong> displayed superior efficacy compared to vancomycin in an <em>in vivo</em> infection model. These findings established <strong>20C</strong> as a promising candidate and underscore the potential of this amphiphilic design strategy in antibiotic discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118674"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153255","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":"Development of the first-in-class RNF4 PROTAC degrader as potential therapeutics for hepatocellular carcinoma","authors":"Hui Wan ,&nbsp;Yihang Liu ,&nbsp;Huimin Chang ,&nbsp;Kai Zhang ,&nbsp;Zhenzhen Li ,&nbsp;Haisen Ni ,&nbsp;Jie Xu ,&nbsp;Bo Pan ,&nbsp;Kongkai Zhu ,&nbsp;Junchi Hu ,&nbsp;Shuai Wang ,&nbsp;Dongqin Yang ,&nbsp;Xiaobo Wang ,&nbsp;Yongjun Dang ,&nbsp;Sanyong Zhu","doi":"10.1016/j.ejmech.2026.118668","DOIUrl":"10.1016/j.ejmech.2026.118668","url":null,"abstract":"<div><div>Ring Finger Protein 4 (RNF4) recognizes poly-SUMOylated proteins via its SUMO-Interacting Motifs (SIMs) and subsequently ubiquitinates them, thus effecting some key regulatory proteins involved in cancer development and progression. Our previous study found RNF4 was a potential target for HCC interruption. However, none of its inhibitor has been developed so far. Targeting RNF4 for degradation, rather than mere binding, emerged as a promising alternative strategy. To this end, we designed, synthesized and evaluated 28 PROTACs targeting RNF4 based on a reported covalent binder. Among them, <strong>RD12</strong> was identified as the lead compound through a systematic screening. <strong>RD12</strong> showed efficient RNF4 degradation activity as well as potent anti-proliferative activity in multiple HCC cell lines. Notably, it exhibited significant anti-tumour activity in a HCC mouse model without noticeable side effects. Mechanistic studies confirmed <strong>RD12</strong> degraded RNF4 via the ubiquitin-proteasome system, and it induced DNA damage and apoptosis. These findings collectively underscore <strong>RD12</strong> as the first pioneering RNF4 degrader and indicate its potential for HCC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118668"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153097","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 novel structural imidazolylvinylquinolones exerting excellent broad-spectrum antibacterial efficacy with multitargeting potential","authors":"Yi-Min Tan ,&nbsp;Aisha Bibi ,&nbsp;Jin-Ping Chen ,&nbsp;Wei-Wei Gao ,&nbsp;Yu Cheng ,&nbsp;Cheng-He Zhou","doi":"10.1016/j.ejmech.2026.118643","DOIUrl":"10.1016/j.ejmech.2026.118643","url":null,"abstract":"<div><div>A unique type of imidazolylvinylquinolones (IVQs) as novel structural scaffold were developed which afforded excellent broad-spectrum antibacterial efficacy with multitargeting potential. Most of the prepared IVQs gave high antibacterial activity and broad antibacterial spectrum, and especially ethyl IVQ <strong>14a</strong>, in which the ethyl group was the most suitable fragment among all the investigated substituents to perform the most effective biosupramolecular effect, showed potent antibacterial activity against MRSA (MIC = 0.25 μg/mL), with an enhanced efficacy 16-fold that of ciprofloxacin. Molecule <strong>14a</strong> also demonstrated low drug resistance, hemolysis, and cytotoxicity, and rapidly bactericidal ability. Mechanism evaluation revealed that molecule <strong>14a</strong> could not only interfere with membranous function and form DNA-<strong>14a</strong> supramolecular complex by intercalation that might obstruct DNA replication, but also effectively interact with lactate dehydrogenase <em>via</em> hydrogen bonds which could obstruct the function of enzyme and inhibit bacterial metabolism, thereby exerting potent bactericidal effect. These potential multitargeting antibacterial actions enabled ethyl IVQ <strong>14a</strong> to exhibit stronger anti-MRSA efficacy without the obvious development of bacterial resistance than ciprofloxacin <em>in vivo</em>. This series of medicinal chemobiological evaluation towards the topic compounds strongly suggested the development potential of unique imidazolylvinylquinolones as novel structural scaffold to combat bacterial resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118643"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109851","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}