Yanhong Wei , Fuqiang Zheng , Lirong Guo , Wenxuan Chen , Hexiang Wang , Longzhu Bao , Zhaoyuan Wu , Ying Li , W. Alateng , Jianglong Su , Mengmeng Kong , Shaoyong Ke
{"title":"Natural pyrrolo[1,2-a]quinazolinone derivatives: Design, synthesis, characterization, and bio-evaluation as novel antiviral agents","authors":"Yanhong Wei , Fuqiang Zheng , Lirong Guo , Wenxuan Chen , Hexiang Wang , Longzhu Bao , Zhaoyuan Wu , Ying Li , W. Alateng , Jianglong Su , Mengmeng Kong , Shaoyong Ke","doi":"10.1016/j.ejmech.2025.117383","DOIUrl":"10.1016/j.ejmech.2025.117383","url":null,"abstract":"<div><div>As viral infectious diseases increasingly threaten global health, antiviral drug research has become a focus in the medicinal chemistry. Enterovirus has always been an important virus causing infections disease with a high incidence in summer and autumn, such as Enterovirus 71 (EV71) and Coxsackievirus B3 (CVB<sub>3</sub>). Currently, no specific antiviral drugs are available for EV71 and CVB<sub>3</sub>. So, we designed and synthesized a novel series of quinazolinone derivatives based on the natural pyrrolo[1,2-<em>a</em>]quinazolinone scaffold, which were fully characterized and identified as potential anti-enterovirus agents. Among them, compound <strong>B9</strong> exhibited potent anti-CVB<sub>3</sub> activity with an EC<sub>50</sub> value of 17.4 ± 3.62 μM, and compound <strong>B5</strong> exhibited potent anti-EV71 activity with an EC<sub>50</sub> value of 14.8 ± 2.18 μM as confirmed by determining the cytopathic effects, progeny virus titers, viral nucleic acid and protein levels. The potential antiviral mechanisms of compound <strong>B5</strong> were also explored. The compound <strong>B5</strong> exhibited a powerful therapeutic effect primarily by blocking the post-attachment stage of viral infection. Further experiments demonstrated that compound <strong>B5</strong> didn't inhibit the activities of the EV71 2Apro and 3Dpol. Modelling of the molecular binding of the 3Cpro-compound complex revealed that the compound <strong>B5</strong> could insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and possibly inhibiting EV71 3Cpro activity. These researches may provide evidence for the development of these novel pyrrolo[1,2-<em>a</em>]quinazolinone derivatives derived from natural products as potential antiviral agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117383"},"PeriodicalIF":6.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418194","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}
Ziquan Zhao , Hongjin Lu , Junjie Wang , Tingting Wu , Shicheng Xu , Yuxin Ge , Qidong You , Zhengyu Jiang , Mengchen Lu
{"title":"Discovery of β-amino acid substituted naphthalene sulfonamide derivatives as potent Kelch-like ECH-associated protein 1−nuclear factor erythroid 2-related factor 2 (Keap1−Nrf2) protein−protein interaction inhibitors for ulcerative colitis management","authors":"Ziquan Zhao , Hongjin Lu , Junjie Wang , Tingting Wu , Shicheng Xu , Yuxin Ge , Qidong You , Zhengyu Jiang , Mengchen Lu","doi":"10.1016/j.ejmech.2025.117384","DOIUrl":"10.1016/j.ejmech.2025.117384","url":null,"abstract":"<div><div>The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense system against oxidative insults. Directly inhibiting the Kelch-like ECH-associated protein 1 (Keap1)−Nrf2 protein−protein interaction (PPI) has emerged as a promising approach to activate Nrf2 for the treatment of diseases associated with oxidative stress. Herein, we identified β-amino acids as privileged structural fragments for designing novel naphthalene sulfonamide-based Keap1−Nrf2 PPI inhibitors. Comprehensive structure−activity relationship (SAR) exploration identified compound <strong>19</strong> as the optimal inhibitor with an IC<sub>50</sub> of 0.55 μM for disrupting the Keap1−Nrf2 interaction and a <em>K</em><sub>d</sub> of 0.50 μM for binding to Keap1. Further studies demonstrated that <strong>19</strong> effectively activated the Nrf2-regulated cytoprotective system and provided protective effects against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in both <em>in vitro</em> and <em>in vivo</em> models. These findings highlight the potential of β-amino acid substituted naphthalene sulfonamide Keap1−Nrf2 inhibitor <strong>19</strong> as a prospective therapeutic agent for UC via Keap1 targeting.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117384"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401886","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, synthesis, and biological evaluation of β-carboline derivatives as ABCB1 inhibitors for reversing multidrug resistance","authors":"Yuanyuan Wang , Nanjin Ding , Yunpeng Zhao, Fengqing Wang, Wen Liu, Zhe Chen, Weiguang Sun, Lianghu Gu, Yonghui Zhang","doi":"10.1016/j.ejmech.2025.117390","DOIUrl":"10.1016/j.ejmech.2025.117390","url":null,"abstract":"<div><div>The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of <em>β</em>-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound <strong>K27</strong> significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC<sub>50</sub> = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The <em>in vitro</em> studies indicated that compound <strong>K27</strong> distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound <strong>K27</strong> was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound <strong>K27</strong> and PTX exhibited potent tumor suppression <em>in vivo</em> without generating toxicity. These results demonstrated that <em>β</em>-carboline compounds represented by compound <strong>K27</strong> may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117390"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401885","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}
Siyu Xiu , Zhenyu Jia , Zhiqi Wang , Huiyu Liu , Cheng Shi , Xiaojiao Sun , Xiangyu Zhang , Xiaowei Chi , Zhenming Liu , Liangren Zhang
{"title":"Design, synthesis, and antitumor activity of NSDs inhibitors targeting lung squamous cell carcinoma","authors":"Siyu Xiu , Zhenyu Jia , Zhiqi Wang , Huiyu Liu , Cheng Shi , Xiaojiao Sun , Xiangyu Zhang , Xiaowei Chi , Zhenming Liu , Liangren Zhang","doi":"10.1016/j.ejmech.2025.117388","DOIUrl":"10.1016/j.ejmech.2025.117388","url":null,"abstract":"<div><div>Lung squamous cell carcinoma (LUSC), a highly aggressive subtype of lung cancer, presents significant therapeutic challenges due to its complex molecular underpinnings. Recently, NSD3 has been identified as a key driver in the pathogenesis of LUSC, providing a new direction for targeted interventions. Herein, we report the rational design, synthesis, and comprehensive biological evaluation of a series of NSD3 inhibitors, culminating in the identification of compound <strong>A8</strong>, which demonstrates potent inhibitory activity against NSD3 and LUSC cell proliferation, with an IC<sub>50</sub> of 0.355 μM in NCI–H1703 cells, and less toxicity to non-cancerous HEK293T cells. Cellular thermal shift assays confirmed the binding affinity of compound <strong>A8</strong> for NSD3, promoting protein stabilization. Mechanistic investigations revealed that compound <strong>A8</strong> induces apoptosis in LUSC cells in a dose-dependent manner and exhibits significant antitumor effects in both <em>in vitro</em> and <em>in vivo</em> models. Notably, compound <strong>A8</strong> displayed favorable pharmacokinetic properties and efficaciously suppressed tumor growth in an NCI–H520 xenograft mouse model without observable adverse effects. These findings collectively establish compound <strong>A8</strong> as a promising candidate for the development of targeted therapies against LUSC, highlighting the therapeutic potential of NSD3 inhibition.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117388"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401891","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}
Yue Xu , Hang Yang , Yunxuan Li , Yuying Qi , Fangling Zhao , Yun Hong , Binbin Cheng , Zebei Lu , Jiaming Zhang , Chunyi Guo , Jie Fu , Qinrong Lin , Chunhong Chen , Ningning Shi , Jianping Cai , Ke Li , Shuanghu Wang , Ruijuan Gao , Dapeng Dai
{"title":"Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity","authors":"Yue Xu , Hang Yang , Yunxuan Li , Yuying Qi , Fangling Zhao , Yun Hong , Binbin Cheng , Zebei Lu , Jiaming Zhang , Chunyi Guo , Jie Fu , Qinrong Lin , Chunhong Chen , Ningning Shi , Jianping Cai , Ke Li , Shuanghu Wang , Ruijuan Gao , Dapeng Dai","doi":"10.1016/j.ejmech.2025.117381","DOIUrl":"10.1016/j.ejmech.2025.117381","url":null,"abstract":"<div><div>Translational readthrough (TR) regulation has emerged as a promising therapeutic strategy for cancer treatment. Utilizing a constructed monoclonal cell line AG-9, designed for screening compounds that induce TR, we identified a BRD4-targeted PROTAC molecule, dBET57, that promotes TR by degrading GSPT1. Notably, dBET57 exhibited significant antiproliferative activity against acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cells across a diverse panel of tumor cell lines. Building on these findings, we optimized the structure of dBET57, leading to the development of analogs with enhanced dual-target degradation capabilities. Most of these optimized degraders demonstrated superior antiproliferative activity in vitro against various AML and NHL cell lines when compared to dBET57. Among them, DP-15 emerged as a particularly promising candidate, exhibiting significant anticancer activity against both AML and NHL cells while maintaining acceptable safety profiles for normal leukocytes. Furthermore, DP-15 demonstrated enhanced antitumor efficacy in mouse cell-derived xenograft (CDX) models. Our findings highlight the potential of dual BRD4 and GSPT1 degraders, such as DP-15, as effective therapeutic agents for the treatment of hematological malignancies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117381"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401890","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}
Santo Previti , Elsa Calcaterra , Carla Di Chio , Benito Natale , Muhammad Waqas , Marta Bogacz , Tanja Schirmeister , Florine Cavelier , Maria Luisa Calabrò , Sandro Cosconati , Roberta Ettari , Maria Zappalà
{"title":"Identification of constrained peptidomimetics carrying a Michael acceptor warhead as antitrypanosomal agents","authors":"Santo Previti , Elsa Calcaterra , Carla Di Chio , Benito Natale , Muhammad Waqas , Marta Bogacz , Tanja Schirmeister , Florine Cavelier , Maria Luisa Calabrò , Sandro Cosconati , Roberta Ettari , Maria Zappalà","doi":"10.1016/j.ejmech.2025.117389","DOIUrl":"10.1016/j.ejmech.2025.117389","url":null,"abstract":"<div><div>In this structure-activity relationship (SAR) study, we report the development of rhodesain-targeting peptidomimetics with antitrypanosomal activity. The new compounds (<strong>SPR65</strong>-<strong>SPR80</strong>) feature the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) moiety as conformationally constrained Phe analog. Various substituents were inserted at the P1 and P3 positions, and the methyl vinyl ketone moiety was introduced as warhead. The incorporation of Tic resulted in reduced affinity against rhodesain compared to the parent compounds containing Phe (<strong>2a-m</strong>), suggesting that its rigidity negatively affects target binding. Nevertheless, promising EC<sub>50</sub> values ranging from 0.42 to 1.35 μM were observed in cell-based assays, probably due to better pharmacokinetic properties and/or interactions with additional protozoal targets. CC<sub>50</sub> values > 100 μM were observed. Therefore, while Tic is less tolerated by rhodesain, its incorporation in peptidomimetic Michael acceptors led to antitrypanosomal effects that were comparable or slightly better than those of the parent compounds and no cytotoxicity up to 100 μM. These findings could be taken into consideration in future SAR studies aimed at the development of antitrypanosomal agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117389"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiefu Wang , Ning Wang , Mengmeng Wang , Ning Liu , Chenyang Wang , Ning Li , Linrong Mu , Yurui Jiang , Jia Chen , Jinxiao Li , Guang Yang , Junfeng Wang , Shuangwei Liu , Kun Zhang
{"title":"Discovery of novel sitolactone derivative leading to PANoptosis and differentiation of acute myeloid leukemia cells","authors":"Jiefu Wang , Ning Wang , Mengmeng Wang , Ning Liu , Chenyang Wang , Ning Li , Linrong Mu , Yurui Jiang , Jia Chen , Jinxiao Li , Guang Yang , Junfeng Wang , Shuangwei Liu , Kun Zhang","doi":"10.1016/j.ejmech.2025.117360","DOIUrl":"10.1016/j.ejmech.2025.117360","url":null,"abstract":"<div><div>Acute Myeloid Leukemia (AML) is a devastating hematologic malignancy. Chemotherapy remains the primary treatment, offering rapid disease control and potential complete remission. However, more than half of the patients develop resistance and relapse, significantly reducing patient survival. Research has shown that drug-resistance and recurrence of AML are closely linked to leukemic stemness. Consequently, discovering new anti-Leukemia stem cell (LSC) compounds is a promising strategy for the treatment of AML in clinic. Additionally, the recent focus on inducing non-apoptotic programmed cell death in AML cells presents an alternative direction for therapeutic drug development, targeting current anti-apoptotic pathways. In this study, novel Sitolactone analogues, potential <em>anti</em>-LSCs compounds, were designed and synthesized based on the “biomimetic design” strategy. Compound <strong>42</strong> was found to significantly inhibit proliferation of AML cells. Subsequent biological evaluation revealed that this compound not only reduced the population of LSCs but also effectively induced PANoptosis in AML cells. Given the active compound's poor water solubility, a prodrug modification strategy was employed to enhance <em>in vivo</em> delivery with superior oral bioavailability and PK properties. This approach significantly suppressed AML cell growth in a mouse orthotropic model with favorable <em>in vivo</em> tolerance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117360"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401888","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}
Yanguo Shang , Miaomiao Pang , Shengnan Fu , Wenjuan Fei , Boxuan Chen , Yaoyao Zhang , Jinxin Wang , Tao Shen
{"title":"Design, synthesis and biological evaluation of pyrrolopyrimidine urea derivatives as novel KRASG12C inhibitors for the treatment of cancer","authors":"Yanguo Shang , Miaomiao Pang , Shengnan Fu , Wenjuan Fei , Boxuan Chen , Yaoyao Zhang , Jinxin Wang , Tao Shen","doi":"10.1016/j.ejmech.2025.117391","DOIUrl":"10.1016/j.ejmech.2025.117391","url":null,"abstract":"<div><div>The KRAS<sup>G12C</sup> mutation, which occurs in approximately 14 % of lung adenocarcinomas, has recently become a crucial target for therapy via small molecules that covalently bind to the mutated cysteine. In this study, a novel series of pyrrolopyrimidine derivatives was rationally designed and synthesized, employing a structure-based drug design strategy. Through structure-activity relationship (SAR) analysis, compound <strong>SK-17</strong> emerged as a direct and highly potent inhibitor of KRAS<sup>G12C</sup>. Cellular assays illustrated that <strong>SK-17</strong> exhibits potent antiproliferative effects, induces apoptosis, possesses anti-tumor metastasis properties, and effectively inhibits the downstream KRAS pathway in a dose-dependent manner. Moreover, the synergistic enhancement observed when <strong>SK-17</strong> is combined with SHP2 inhibitors in vitro underscores its innovative potential in combinatorial therapies. In the xenograft mouse model, <strong>SK-17</strong> demonstrated outstanding tumor growth suppression with good safety. Importantly, the in vivo test results show that compound SK-17 has a superior PK profile and lower toxicity in zebrafish test. These results demonstrated the potential of <strong>SK-17</strong> with novel scaffold as a promising lead compound targeting KRAS<sup>G12C</sup> to guide in-depth structural optimization.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117391"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401889","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}
Rasha Z. Batran , Manal S. Ebaid , Sherry N. Nasralla , Ninh The Son , Nguyen Xuan Ha , Hoda Atef Abdelsattar Ibrahim , Mahmoud Abdelrahman Alkabbani , Yusuke Kasai , Hiroshi Imagawa , Mohammad M. Al-Sanea , Tamer M. Ibrahim , Abdelsamed I. Elshamy , Adnan A. Bekhit , Wagdy M. Eldehna , Ahmed Sabt
{"title":"Synthesis and mechanistic insights of Coumarinyl-Indolinone hybrids as potent inhibitors of Leishmania major","authors":"Rasha Z. Batran , Manal S. Ebaid , Sherry N. Nasralla , Ninh The Son , Nguyen Xuan Ha , Hoda Atef Abdelsattar Ibrahim , Mahmoud Abdelrahman Alkabbani , Yusuke Kasai , Hiroshi Imagawa , Mohammad M. Al-Sanea , Tamer M. Ibrahim , Abdelsamed I. Elshamy , Adnan A. Bekhit , Wagdy M. Eldehna , Ahmed Sabt","doi":"10.1016/j.ejmech.2025.117392","DOIUrl":"10.1016/j.ejmech.2025.117392","url":null,"abstract":"<div><div>Leishmaniasis, recognized as a neglected tropical disease, is a major global health issue that impacts millions of individuals across the globe. The limitations of existing treatments underscore the urgent need for novel antileishmanial drugs. In response, this study synthesized and evaluated fifteen hybrid compounds (<strong>7a-c</strong>, <strong>10a-j</strong>, and <strong>13a-b</strong>) combining 4-hydroxycoumarin and pyrazolyl indolin-2-one motifs for their <em>in vitro</em> antileishmanial efficacy towards <em>Leishmania major</em>. These molecules demonstrated remarkable activity against the promastigote form, with IC<sub>50</sub> values ranging from 1.21 to 7.21 μM, surpassing the reference drug miltefosine (IC<sub>50</sub> = 7.83 μM). Assessment against the intracellular amastigote form revealed efficient inhibitory action (IC<sub>50</sub>: 2.41–9.44 μM vs. 8.07 μM for miltefosine). Compounds <strong>7a</strong> and <strong>7b</strong> exhibited exceptional antileishmanial activity against both forms while maintaining favorable safety profiles. Mechanistic studies indicated that the most effective compounds act through an antifolate mechanism, targeting pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Molecular docking and dynamics simulations of compounds <strong>7a</strong> and <strong>7b</strong> revealed strong in-silico binding and stable dynamics against PTR1, suggesting a high potential for enzyme inhibition. These findings present a promising new class of antileishmanial agents targeting the folate pathway.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117392"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393993","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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