European Journal of Medicinal Chemistry最新文献

英文中文

Discovery of novel sitolactone derivative leading to PANoptosis and differentiation of acute myeloid leukemia cells

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-12 DOI: 10.1016/j.ejmech.2025.117360

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

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 anti-LSCs compounds, were designed and synthesized based on the “biomimetic design” strategy. Compound 42 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 in vivo delivery with superior oral bioavailability and PK properties. This approach significantly suppressed AML cell growth in a mouse orthotropic model with favorable in vivo tolerance.

{"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}

引用次数: 0

Design, synthesis and biological evaluation of pyrrolopyrimidine urea derivatives as novel KRASG12C inhibitors for the treatment of cancer

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-12 DOI: 10.1016/j.ejmech.2025.117391

Yanguo Shang , Miaomiao Pang , Shengnan Fu , Wenjuan Fei , Boxuan Chen , Yaoyao Zhang , Jinxin Wang , Tao Shen

The KRAS^G12C 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 SK-17 emerged as a direct and highly potent inhibitor of KRAS^G12C. Cellular assays illustrated that SK-17 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 SK-17 is combined with SHP2 inhibitors in vitro underscores its innovative potential in combinatorial therapies. In the xenograft mouse model, SK-17 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 SK-17 with novel scaffold as a promising lead compound targeting KRAS^G12C to guide in-depth structural optimization.

{"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}

引用次数: 0

Synthesis and mechanistic insights of Coumarinyl-Indolinone hybrids as potent inhibitors of Leishmania major

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-12 DOI: 10.1016/j.ejmech.2025.117392

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

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 (7a-c, 10a-j, and 13a-b) combining 4-hydroxycoumarin and pyrazolyl indolin-2-one motifs for their in vitro antileishmanial efficacy towards Leishmania major. These molecules demonstrated remarkable activity against the promastigote form, with IC₅₀ values ranging from 1.21 to 7.21 μM, surpassing the reference drug miltefosine (IC₅₀ = 7.83 μM). Assessment against the intracellular amastigote form revealed efficient inhibitory action (IC₅₀: 2.41–9.44 μM vs. 8.07 μM for miltefosine). Compounds 7a and 7b 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 7a and 7b 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.

{"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}

引用次数: 0

Emerging drugs for Epstein-Barr virus associated-diseases

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-11 DOI: 10.1016/j.ejmech.2025.117386

Nassima Oumata , Qian Zhong , Yongmin Zhang , Hervé Galons , Graciela Andrei , Musheng Zeng

Epstein-Barr virus (EBV) is the first identified oncogenic virus. It causes three types of diseases: lymphomas, carcinomas, and autoimmune diseases. It is estimated that two hundred thousand deaths are due to EBV each year. After a primary infection, EBV can remain latent lifelong. Reactivation to lytic phase can be induced by various drugs including small organic molecules, biologics, or a combination of both. In this review, we identified the most relevant results obtained with small organic compounds against Epstein-Barr virus-associated diseases. Specific treatments targeting Epstein-Barr Nuclear Antigen 1 are emerging concerning small organic molecules and showed promising results against several EBV-related malignancies.

引用次数: 0

Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-10 DOI: 10.1016/j.ejmech.2025.117378

Meng Xia , Ziteng Li , Hanrui Jiang , Yuanqing Li , Linghao Hu , Yongchang He , Siqi Huang , Lei Tang , Cheng Luo , Shuangxi Gu , Hong Ding , Mingliang Wang

Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive subtype of breast cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-b]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells. Among these compounds, compound 24 emerged as the most potent inhibitor, with CDK12 IC₅₀ of 15.5 nM and CDK13 IC₅₀ of 12.2 nM. Compound 24 forms a covalent bond with Cys1039 of CDK12 and effectively suppresses the proliferation of TNBC cell lines MDA-MB-231 and MDA-MB-468, with EC₅₀ values of 5.0 nM and 6.0 nM, respectively. Compound 24 demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound 24 may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.

{"title":"Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13","authors":"Meng Xia , Ziteng Li , Hanrui Jiang , Yuanqing Li , Linghao Hu , Yongchang He , Siqi Huang , Lei Tang , Cheng Luo , Shuangxi Gu , Hong Ding , Mingliang Wang","doi":"10.1016/j.ejmech.2025.117378","DOIUrl":"10.1016/j.ejmech.2025.117378","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive subtype of breast cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-<em>b</em>]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells. Among these compounds, compound <strong>24</strong> emerged as the most potent inhibitor, with CDK12 IC<sub>50</sub> of 15.5 nM and CDK13 IC<sub>50</sub> of 12.2 nM. Compound <strong>24</strong> forms a covalent bond with Cys1039 of CDK12 and effectively suppresses the proliferation of TNBC cell lines MDA-MB-231 and MDA-MB-468, with EC<sub>50</sub> values of 5.0 nM and 6.0 nM, respectively. Compound <strong>24</strong> demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound <strong>24</strong> may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117378"},"PeriodicalIF":6.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375230","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}

引用次数: 0

Highlights on U.S. FDA-approved halogen-containing drugs in 2024

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-09 DOI: 10.1016/j.ejmech.2025.117380

Saghir Ali, Xiaochen Tian, Salvatore A. Meccia, Jia Zhou

This comprehensive review offers an update on the FDA-approved halogen-containing drugs in 2024. The agency approved a total of 50 drugs, including small molecules and macromolecules. Excitingly, 16 out of 50 are halogen-containing drugs, indicated to diagnose, mitigate and treat the various human diseases. Among halogens, fluorine and chlorine are highly prevalent in drug discovery and development. Therefore, the properties of fluorine and chlorine and their impact on the drug profile are briefly discussed. In addition, the specific role of halogens in these drugs has been discussed with the help of structure-activity relationships (SARs), co-crystal structures, and closely related literature precedents. This review also provides the additional information for each drug, such as trade name, active ingredients, route of administration, approval date, sponsors, indication, mode of action, major drug metabolizing enzyme(s), and route of elimination. We expect that the present review may garner the attention of drug discovery researchers and inspire them toward the potential applications of halogens to discover novel therapeutics in the future.

{"title":"Highlights on U.S. FDA-approved halogen-containing drugs in 2024","authors":"Saghir Ali, Xiaochen Tian, Salvatore A. Meccia, Jia Zhou","doi":"10.1016/j.ejmech.2025.117380","DOIUrl":"10.1016/j.ejmech.2025.117380","url":null,"abstract":"<div><div>This comprehensive review offers an update on the FDA-approved halogen-containing drugs in 2024. The agency approved a total of 50 drugs, including small molecules and macromolecules. Excitingly, 16 out of 50 are halogen-containing drugs, indicated to diagnose, mitigate and treat the various human diseases. Among halogens, fluorine and chlorine are highly prevalent in drug discovery and development. Therefore, the properties of fluorine and chlorine and their impact on the drug profile are briefly discussed. In addition, the specific role of halogens in these drugs has been discussed with the help of structure-activity relationships (SARs), co-crystal structures, and closely related literature precedents. This review also provides the additional information for each drug, such as trade name, active ingredients, route of administration, approval date, sponsors, indication, mode of action, major drug metabolizing enzyme(s), and route of elimination. We expect that the present review may garner the attention of drug discovery researchers and inspire them toward the potential applications of halogens to discover novel therapeutics in the future.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117380"},"PeriodicalIF":6.0,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371609","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}

引用次数: 0

Synthesis and evaluation of piceatannol derivatives as novel arginase inhibitors with radical scavenging activity and their potential for collagen reduction in dermal fibroblasts

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-09 DOI: 10.1016/j.ejmech.2025.117376

Luca Marchisio , Quentin Gaudillat , Jason Muller , Andy Zedet , Marion Tissot , Dominique Harakat , François Sénéjoux , Gwenaël Rolin , Bruno Cardey , Corine Girard , Marc Pudlo

High arginase activity is associated with several pathological conditions, including TGF-β-induced fibrosis, by increasing levels of the proline precursor l-ornithine, thereby promoting collagen biosynthesis and increasing oxidative stress due to nitric oxide synthase (NOS) uncoupling. The natural piceatannol has been shown to have beneficial effects on collagen deposition, fibrosis and oxidative stress. In this study, we present an in-depth structure-activity relationship study on arginase I, which resulted in the thioamide derivative 12a with dual catechol rings that displays potent inhibitory activity with IC₅₀ values of 9 μM and 55 μM for bovine and human arginase I, respectively. Quantum chemical modelling suggested that the sulphur atom in the thioamide group plays a crucial role in binding affinity by forming a stable hydrogen bond within the active site of the enzyme. In addition, compound 12a demonstrated high radical scavenging activity and effectively normalised collagen and procollagen levels at 5 μM in an in vitro cell model of a dermal fibrosis.

{"title":"Synthesis and evaluation of piceatannol derivatives as novel arginase inhibitors with radical scavenging activity and their potential for collagen reduction in dermal fibroblasts","authors":"Luca Marchisio , Quentin Gaudillat , Jason Muller , Andy Zedet , Marion Tissot , Dominique Harakat , François Sénéjoux , Gwenaël Rolin , Bruno Cardey , Corine Girard , Marc Pudlo","doi":"10.1016/j.ejmech.2025.117376","DOIUrl":"10.1016/j.ejmech.2025.117376","url":null,"abstract":"<div><div>High arginase activity is associated with several pathological conditions, including TGF-β-induced fibrosis, by increasing levels of the proline precursor <span>l</span>-ornithine, thereby promoting collagen biosynthesis and increasing oxidative stress due to nitric oxide synthase (NOS) uncoupling. The natural piceatannol has been shown to have beneficial effects on collagen deposition, fibrosis and oxidative stress. In this study, we present an in-depth structure-activity relationship study on arginase I, which resulted in the thioamide derivative <strong>12a</strong> with dual catechol rings that displays potent inhibitory activity with IC₅₀ values of 9 μM and 55 μM for bovine and human arginase I, respectively. Quantum chemical modelling suggested that the sulphur atom in the thioamide group plays a crucial role in binding affinity by forming a stable hydrogen bond within the active site of the enzyme. In addition, compound <strong>12a</strong> demonstrated high radical scavenging activity and effectively normalised collagen and procollagen levels at 5 μM in an <em>in vitro</em> cell model of a dermal fibrosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117376"},"PeriodicalIF":6.0,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371608","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}

引用次数: 0

Discovery of novel thiazole-pleuromutilin derivatives with potent antibacterial activity

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-08 DOI: 10.1016/j.ejmech.2025.117374

Xian-Long Qi, He-Chao Zhang, Xiao Xu, Xi-Wang Liu, Ya-Jun Yang, Zhun Li, Jian-Yong Li

A series of novel thiazole-pleuromutilin derivatives were designed and synthesized, and their antibacterial activities were evaluated. Most of the synthesized derivatives showed good activity against Gram-positive bacteria, among which compound h19 was more prominent and had the strongest antibacterial activity against MRSA. Compound h19 was selected for further evaluation of bacterial time-kill kinetics, and the results demonstrated its highly promising efficacy in inhibiting MRSA growth. Moreover, h19 exhibited a superior post-antibiotic effect (PAE) value and a lower possibility for bacterial resistance development compared to tiamulin. Docking studies demonstrated the strong affinity of h19 for the 50S ribosomal subunit with a binding free energy of −10.6 kcal/mol. The cytotoxic assay indicated that h19 had low cytotoxicity on both HEK293T and HepG2 cells (IC₅₀ > 200 μM). In MRSA systemic-infected mouse model, h19 improved survival rates, reduced the bacterial load, and alleviated pathological changes in the lungs of the infected mice, which exhibited a more potent antibacterial efficacy compared to tiamulin. Compound h19 also displayed low oral toxicity with an LD₅₀ value more than 2000 mg/kg.

{"title":"Discovery of novel thiazole-pleuromutilin derivatives with potent antibacterial activity","authors":"Xian-Long Qi, He-Chao Zhang, Xiao Xu, Xi-Wang Liu, Ya-Jun Yang, Zhun Li, Jian-Yong Li","doi":"10.1016/j.ejmech.2025.117374","DOIUrl":"10.1016/j.ejmech.2025.117374","url":null,"abstract":"<div><div>A series of novel thiazole-pleuromutilin derivatives were designed and synthesized, and their antibacterial activities were evaluated. Most of the synthesized derivatives showed good activity against Gram-positive bacteria, among which compound <strong>h19</strong> was more prominent and had the strongest antibacterial activity against MRSA. Compound <strong>h19</strong> was selected for further evaluation of bacterial time-kill kinetics, and the results demonstrated its highly promising efficacy in inhibiting MRSA growth. Moreover, <strong>h19</strong> exhibited a superior post-antibiotic effect (PAE) value and a lower possibility for bacterial resistance development compared to tiamulin. Docking studies demonstrated the strong affinity of <strong>h19</strong> for the 50S ribosomal subunit with a binding free energy of −10.6 kcal/mol. The cytotoxic assay indicated that <strong>h19</strong> had low cytotoxicity on both HEK293T and HepG2 cells (IC<sub>50</sub> > 200 μM). In MRSA systemic-infected mouse model, <strong>h19</strong> improved survival rates, reduced the bacterial load, and alleviated pathological changes in the lungs of the infected mice, which exhibited a more potent antibacterial efficacy compared to tiamulin. Compound <strong>h19</strong> also displayed low oral toxicity with an LD<sub>50</sub> value more than 2000 mg/kg.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117374"},"PeriodicalIF":6.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367626","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}

引用次数: 0

Discovery of naphthoquinone-furo-piperidone derivatives as dual targeting agents of STAT3 and NQO1 for the treatment of breast cancer

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-07 DOI: 10.1016/j.ejmech.2025.117377

Shengying Lou , Chenjun Shen , Hao Ni , Chengcheng Fan , Zhihui Zhu , Xueping Hu , Huajun Zhao , Sunliang Cui

Breast cancer is one of the most common malignancies in women, posing a significant threat to their physical and mental well-being. STAT3 has been found closely associated with the occurrence and development of breast cancer, while blocking STAT3 pathway can promote apoptosis of breast cancer cells and inhibit cell proliferation. NQO1 is a potential anti-tumor drug target, and its substrate has been widely proven to show significant anti-tumor activity. Thus, those agents that could simultaneously target STAT3 and NQO1 might provide a new approach for the treatment of breast cancer. Herein, we have designed and synthesized novel naphthoquinone-furo-piperidone derivatives as dual targeting agents of STAT3 and NQO1. The anti-proliferative activity evaluation revealed that most of these compounds exhibited superior inhibitory activity against MDA-MB-231 and MDA-MB-468 breast cancer cell lines compared to napabucasin. In particular, the promising compound 16c was found to significantly inhibit phosphorylation of STAT3 at Tyr705 at a concentration of 1 μM and effectively induce apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells. Moreover, 16c was also found as a NQO1 substrate to strongly increase ROS generation and cause severe DNA damage in a dose-dependent manner. Meanwhile, 16c showed encouraging anti-tumor efficacy in the MDA-MB-231 xenograft model. In summary, this protocol provides a new vision and new chemical entity for dual targeting STAT3 and NQO1.

{"title":"Discovery of naphthoquinone-furo-piperidone derivatives as dual targeting agents of STAT3 and NQO1 for the treatment of breast cancer","authors":"Shengying Lou , Chenjun Shen , Hao Ni , Chengcheng Fan , Zhihui Zhu , Xueping Hu , Huajun Zhao , Sunliang Cui","doi":"10.1016/j.ejmech.2025.117377","DOIUrl":"10.1016/j.ejmech.2025.117377","url":null,"abstract":"<div><div>Breast cancer is one of the most common malignancies in women, posing a significant threat to their physical and mental well-being. STAT3 has been found closely associated with the occurrence and development of breast cancer, while blocking STAT3 pathway can promote apoptosis of breast cancer cells and inhibit cell proliferation. NQO1 is a potential anti-tumor drug target, and its substrate has been widely proven to show significant anti-tumor activity. Thus, those agents that could simultaneously target STAT3 and NQO1 might provide a new approach for the treatment of breast cancer. Herein, we have designed and synthesized novel naphthoquinone-furo-piperidone derivatives as dual targeting agents of STAT3 and NQO1. The anti-proliferative activity evaluation revealed that most of these compounds exhibited superior inhibitory activity against MDA-MB-231 and MDA-MB-468 breast cancer cell lines compared to napabucasin. In particular, the promising compound <strong>16c</strong> was found to significantly inhibit phosphorylation of STAT3 at Tyr705 at a concentration of 1 μM and effectively induce apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells. Moreover, <strong>16c</strong> was also found as a NQO1 substrate to strongly increase ROS generation and cause severe DNA damage in a dose-dependent manner. Meanwhile, <strong>16c</strong> showed encouraging anti-tumor efficacy in the MDA-MB-231 xenograft model. In summary, this protocol provides a new vision and new chemical entity for dual targeting STAT3 and NQO1.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117377"},"PeriodicalIF":6.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257862","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}

引用次数: 0

Application of deuterium in research and development of drugs

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-07 DOI: 10.1016/j.ejmech.2025.117371

Jiong Chen , Yuan-Yuan Zhu , Lu Huang , Shuang-Shuang Zhang , Shuang-Xi Gu

Deuterium is gaining increased attention and utilization due to its unique physical and chemical properties. Deuteration has the unique benefit of positively impacting metabolic fate of pharmacologically active compounds without altering their chemical structures, physical properties, or biological activity and selectivity. In these favorable cases, deuterium substitution can in principle improve the pharmacokinetic properties and safety of therapeutic agents. The use of deuterium to create a new chemical entity not only starts with an existing drug, but can be achieved from iterative optimization in the de novo design of new compounds. Furthermore, deuterium has become a powerful tool in pharmaceutical analysis, including deuterium-labeled compounds as internal standards for extensive analysis, metabolomics, ADME, clinical pharmacology studies. This review highlights the application of deuterium in enhancing the pharmacological effects of active molecules during drug discovery and development. Additionally, deuterium-enabled pharmaceutical analysis is also covered. This review is aimed to provide references for the discovery of new deuterium-containing chemical entities with improved pharmacological properties and for the research of fate of drugs.

{"title":"Application of deuterium in research and development of drugs","authors":"Jiong Chen , Yuan-Yuan Zhu , Lu Huang , Shuang-Shuang Zhang , Shuang-Xi Gu","doi":"10.1016/j.ejmech.2025.117371","DOIUrl":"10.1016/j.ejmech.2025.117371","url":null,"abstract":"<div><div>Deuterium is gaining increased attention and utilization due to its unique physical and chemical properties. Deuteration has the unique benefit of positively impacting metabolic fate of pharmacologically active compounds without altering their chemical structures, physical properties, or biological activity and selectivity. In these favorable cases, deuterium substitution can in principle improve the pharmacokinetic properties and safety of therapeutic agents. The use of deuterium to create a new chemical entity not only starts with an existing drug, but can be achieved from iterative optimization in the <em>de novo</em> design of new compounds. Furthermore, deuterium has become a powerful tool in pharmaceutical analysis, including deuterium-labeled compounds as internal standards for extensive analysis, metabolomics, ADME, clinical pharmacology studies. This review highlights the application of deuterium in enhancing the pharmacological effects of active molecules during drug discovery and development. Additionally, deuterium-enabled pharmaceutical analysis is also covered. This review is aimed to provide references for the discovery of new deuterium-containing chemical entities with improved pharmacological properties and for the research of fate of drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117371"},"PeriodicalIF":6.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367627","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}

引用次数: 0

首页上一页

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

European Journal of Medicinal Chemistry

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀