European Journal of Medicinal Chemistry最新文献

{"title":"Novel frontiers through nitrogen substitution at 6th, 10th and 11th position of artemisinin: Synthetic approaches and antimalarial activity","authors":"Priyanka Yadav ,&nbsp;Varun Rawat ,&nbsp;Shalini Kaushik Love ,&nbsp;Ved Prakash Verma","doi":"10.1016/j.ejmech.2024.117032","DOIUrl":"10.1016/j.ejmech.2024.117032","url":null,"abstract":"<div><div>Malaria pertains to an array of catastrophic illnesses spurred on by the <em>Plasmodium</em> spp. Artemisinin (ART) is currently prescribed in conjunction with another medication as part of therapeutic regimens for acute malaria. These currently prescribed pharmaceuticals have been around for a while, even after lack of required thermos-metabolic stabilities, alongside fresh proclaims about surfacing resistance and neurotoxicity linked with sequential administration of such combination therapies. Over the years, ARTs seem to have gained popularity through the accelerated reduction in parasitaemia, thus dictating use of differentially stable ART derivatives, in combination or alone, to control the proliferation of malaria. The endoperoxide bridge in the ART pharmacophore plays a non-negotiable role in its action against multiple stages in the parasitic life cycle. However, shorter half-lives and limited bioavailability tend to open doors for another class of endoperoxides. Nitrogen substitution at 6th, 10th and 11th positions of ART draws attention as the best replacements through their disparate stabilities and inability to demonstrate <em>in vivo</em> hydrolytic decomposition into DHA. Discussions pertaining such azaartemisinins and aminoartemisinins reported over the past 30 years have been strongly focused upon, on account of their synthetic methodologies and antimalarial efficacies, in order to assign future candidature to the meritorious moiety.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117032"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596848","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 fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile","authors":"Jiaojiao Dai ,&nbsp;Xiangyi Jiang ,&nbsp;Heng Gao ,&nbsp;Boshi Huang ,&nbsp;Erik De Clercq ,&nbsp;Christophe Pannecouque ,&nbsp;Shaoqing Du ,&nbsp;Xinyong Liu ,&nbsp;Peng Zhan","doi":"10.1016/j.ejmech.2024.117033","DOIUrl":"10.1016/j.ejmech.2024.117033","url":null,"abstract":"<div><div>As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported <strong>XJ-18b1</strong> as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound <strong>3k</strong> exhibited prominent inhibitory activity against wild-type HIV-1 (EC₅₀ = 0.0019 μM) and common mutant strains including K103 N (EC₅₀ = 0.0019 μM), L100I (EC₅₀ = 0.0087 μM), E138K (EC₅₀ = 0.011 μM), along with low cytotoxicity and high selectivity index (CC₅₀ = 21.95 μM, SI = 11478). Additionally, compound <strong>3k</strong> demonstrated antiviral activity against HIV-2 with EC₅₀ value of 6.14 μM. The enzyme-linked immunosorbent assay validated that <strong>3k</strong> could significantly inhibit the activity of HIV-1 reverse transcriptase (IC₅₀ = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-<strong>3k</strong> complex, and <em>in silico</em> prediction revealed that <strong>3k</strong> possessed favorable drug-like profiles. Collectively, <strong>3k</strong> proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117033"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594472","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 thiosemicarbazone-acridine targeting butyrylcholinesterase with antioxidant, metal complexing and neuroprotector abilities as potential treatment of Alzheimer's disease: In vitro, in vivo, and in silico studies","authors":"Gleyton Leonel Silva Sousa ,&nbsp;Nathalia Fonseca Nadur ,&nbsp;Larissa de Almeida Peixoto Ferreira ,&nbsp;Thiago da Silva Honório ,&nbsp;Alice Simon ,&nbsp;Lucio Mendes Cabral ,&nbsp;Maria Luiza Móra Santos ,&nbsp;Bruna Andrade ,&nbsp;Emanuelle V. de Lima ,&nbsp;Julia R. Clarke ,&nbsp;Rosane Nora Castro ,&nbsp;Ricardo Olímpio de Moura ,&nbsp;Arthur Eugen Kümmerle","doi":"10.1016/j.ejmech.2024.117030","DOIUrl":"10.1016/j.ejmech.2024.117030","url":null,"abstract":"<div><div>Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC₅₀ value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC₅₀ = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC₅₀ = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an <em>in vitro</em> oxidative stress model induced by H₂O₂. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117030"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596874","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 4-(4-(3-(1-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole-2-yl)isoxazol-5-yl)phenyl)morpholine as a novel c-Myc inhibitor against lung cancer in vitro and in vivo","authors":"Jian Gao ,&nbsp;Jiacheng Yin ,&nbsp;Shihao Li ,&nbsp;Pingting Jia,&nbsp;Renjie Hong,&nbsp;Jiahui Chen,&nbsp;Xinxin Qu,&nbsp;Zihui Zhang,&nbsp;Mengting Li,&nbsp;Hui Zhao","doi":"10.1016/j.ejmech.2024.117023","DOIUrl":"10.1016/j.ejmech.2024.117023","url":null,"abstract":"<div><div>The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of <strong>D347</strong>–<strong>2761</strong>, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound <strong>A1</strong> displayed IC₅₀ values of 6.32 μM and 11.39 μM against the A549 and NCI–H1299 lung cancer cell lines, respectively, while compound <strong>A5</strong> exhibited IC₅₀ values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds <strong>A1</strong> and <strong>A5</strong> exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound <strong>A5</strong> demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound <strong>A5</strong> exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound <strong>A5</strong> holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117023"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594539","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 phenyl urea SHP2 inhibitors with anti-colon cancer and potential immunomodulatory effects","authors":"Kaizhen Wang ,&nbsp;Xiangyu Zhang ,&nbsp;Yingxin Hu,&nbsp;Jiazheng Guo,&nbsp;Guoqing Shen,&nbsp;Kuojun Zhang,&nbsp;Sheng Jiang,&nbsp;Tianyu Wang","doi":"10.1016/j.ejmech.2024.117036","DOIUrl":"10.1016/j.ejmech.2024.117036","url":null,"abstract":"<div><div>Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) is a non-receptor-type protein tyrosine phosphatase (PTP), which is recognized as potential and attractive cancer therapeutic target. Currently, no SHP2 inhibitors have been approved for clinical use, and colorectal cancer (CRC) cells exhibited frequent resistance to reported SHP2 inhibitors, such as <strong>SHP099</strong> and <strong>TNO155</strong>. Herein, we reported our discovery and optimization of phenyl urea as novel SHP2 inhibitors. <strong>A8</strong>, the most potential SHP2 inhibitor, exhibited great antiproliferative activities against <strong>SHP099</strong>/<strong>TNO155</strong>-insensitive tumor cell lines, and rescued PD-L1-mediated immunosuppression. <strong>A8</strong> significantly suppressed <em>in vivo</em> tumor growth in a CT26 mouse model and activated immunomodulatory effects in tumor microenvironment. Our work demonstrated that <strong>A8</strong> has the potential to be a lead compound for the further development of SHP2 inhibitor and the treatment of CRC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117036"},"PeriodicalIF":6.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594470","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 glycofullerene derivatives as novel photosensitizer for potential application in PDT to treat cancer","authors":"Xue Bai ,&nbsp;Tian Yang ,&nbsp;Xinle Shao ,&nbsp;Bobo Jia ,&nbsp;Huifang Hao ,&nbsp;Faiz-Ur Rahman ,&nbsp;Yongmin Zhang","doi":"10.1016/j.ejmech.2024.117009","DOIUrl":"10.1016/j.ejmech.2024.117009","url":null,"abstract":"<div><div>Cancer is one of the most aggressive diseases known to humanity, characterized by low survival rates and poor prognoses. Currently, platinum-based anticancer drugs and traditional photosensitizers used in photodynamic therapy (PDT) are the most widely employed treatment modalities. However, the platinum-based medications, particularly cisplatin, the most commonly used agent, have several drawbacks. These drawbacks may include systemic toxicity, which can manifest as nephrotoxicity, neurotoxicity, ototoxicity, or emesis during treatment. Such side effects can severely impair patients and significantly diminish the overall effectiveness of therapeutic interventions. In contrast, photodynamic therapy does not present these disadvantages. PDT offers numerous benefits, including reduced long-term morbidity, minimal systemic toxicity, low invasiveness, negligible drug resistance, and temporal and geographic selectivity, all of which enhance patients' quality of life. Consequently, the search for novel, effective, and practical photosensitizers is essential. Fullerenes possess unique physicochemical properties that make them highly suitable as photosensitizers. In this study, we developed a comprehensive and straightforward synthesis for two water-soluble sugar fullerene derivatives, designated as <strong>12</strong> and <strong>13</strong>. Multiple analytical techniques, including ¹H NMR, ¹³C NMR, high-resolution mass spectrometry (HRMS), Fourier-transform infrared spectroscopy (FT-IR), and ultraviolet–visible (UV–Vis) spectroscopy, collectively confirmed the chemical structures of these derivatives and validated their successful synthesis. Upon exposure to white light irradiation at an intensity of 2.5J/cm², compound <strong>13</strong> demonstrated significant biological activity against three distinct tumor cell lines: HepG2, MKN45, and RPMI 4788, with IC₅₀ values of 5.65 μM, 2.43 μM, and 1.82 μM, respectively. This study establishes a foundation for the development of innovative clinical photosensitizers.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117009"},"PeriodicalIF":6.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594471","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 new fungal jumonji H3K27 demethylase inhibitors for the treatment of Cryptococcus neoformans and Candida auris infections","authors":"Xin Liu ,&nbsp;Wang Li ,&nbsp;Yang Liu ,&nbsp;Xiaoqing Wang ,&nbsp;Qiao Shi ,&nbsp;Wanzhen Yang ,&nbsp;Jie Tu ,&nbsp;Yan Wang ,&nbsp;Chunquan Sheng ,&nbsp;Na Liu","doi":"10.1016/j.ejmech.2024.117028","DOIUrl":"10.1016/j.ejmech.2024.117028","url":null,"abstract":"<div><div>Invasive fungal infections have become a serious public health problem. To tackle the challenges of limited efficacy in antifungal therapy and severe drug resistance, antifungal drugs with new mechanisms of action are urgently needed. Our previous study identified <strong>JIB-04</strong> to be an inhibitor of fungal histone demethylase (HDM). To promote target validation and inhibitor design, herein a series of new <strong>JIB-04</strong> derivatives were designed and synthesized. After the establishment of structure-activity relationship, compound <strong>A4</strong> was identified to possess potent antifungal activity against <em>Cryptococcus neoformans</em> and <em>Candida auris</em>. Compared to lead compound <strong>JIB-04</strong>, compound <strong>A4</strong> was a more potent HDM inhibitor and exhibited better water solubility, virulence factors inhibitory activity and <em>in vivo</em> antifungal potency. Collectively, this study further confirmed that fungal HDMs were potential antifungal targets and compound <strong>A4</strong> was a promising antifungal lead compound.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117028"},"PeriodicalIF":6.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594537","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 pyrrolopyrimidinone derivatives as potent PKMYT1 inhibitors for the treatment of cancer","authors":"Chao Wang ,&nbsp;Yazhou Wang ,&nbsp;Fanye Meng ,&nbsp;Tingting Liu ,&nbsp;Xiaomin Wang ,&nbsp;Xin Cai ,&nbsp;Man Zhang ,&nbsp;Alex Aliper ,&nbsp;Feng Ren ,&nbsp;Alex Zhavoronkov ,&nbsp;Xiao Ding","doi":"10.1016/j.ejmech.2024.117025","DOIUrl":"10.1016/j.ejmech.2024.117025","url":null,"abstract":"<div><div>The protein kinase PKMYT1 is responsible for inhibitory CDK1 phosphorylation, thus playing a central role in regulating the G2/M cell cycle checkpoint. As many cancers have dysfunctional cell cycle checkpoint signaling, PKMYT1 inhibition is emerging as an attractive target in advanced tumors. PKMYT1 inhibitors, however, have encountered difficulties in balancing biological efficacy, on-target specificity, and favorable stability and other drug-like properties. Herein, we report the design and development of pyrrolopyrimidinone derivatives intended to simultaneously restrict molecular conformation and shield a metabolic site in order to optimize stability. Compound <strong>7</strong> demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy <em>in vitro</em>, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor <em>in vivo</em> efficacy. Our findings indicate that compound <strong>7</strong> is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117025"},"PeriodicalIF":6.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580260","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 cytotoxicity screening of novel pyrazolopyrimidines over renal cell carcinoma (UO-31 cells) as p38α inhibitors, and apoptotic cells inducing activities","authors":"Sara Y. Ewieda ,&nbsp;Amr Sonousi ,&nbsp;Aliaa M. Kamal ,&nbsp;Mohamed K. Abdelhamid","doi":"10.1016/j.ejmech.2024.117005","DOIUrl":"10.1016/j.ejmech.2024.117005","url":null,"abstract":"<div><div>A series of novel molecules with pyrazolopyrimidine-4-amine core were designed and synthesized as potential cytotoxic agents over Renal Cell Carcinoma cells (UO-31). Results of cytotoxic activity against UO-31 cells showed that pyrazolopyrimidines <strong>19</strong> and <strong>31</strong> were found to be more cytotoxic than sorafenib (SOR). The cytotoxic activity of these compounds appeared to correlate with their ability to inhibit p38α MAPK which are 2.53- and 2.27- folds more potent than SOR. Moreover, results of the cell cycle analysis as well as the results of annexin-V on the (UO-31) cells showed that pyrazolopyrimidines <strong>19</strong> and <strong>31</strong> had a pro-apoptotic activity higher than SOR by 1.42- and 1.20- folds, respectively. Furthermore, compounds <strong>19</strong> and <strong>31</strong> were found to be effective in arresting the cell cycle throughout the accumulation of the cells at G2/M phase. Finally, the tested compounds decreased the TNF concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117005"},"PeriodicalIF":6.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588325","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 cloxiquine derivatives as potent HDAC inhibitors for the treatment of melanoma via activating PPARγ","authors":"Limin Yang ,&nbsp;Ran Ding ,&nbsp;Xiaojie Tong ,&nbsp;Tong Shen ,&nbsp;Shuting Jia ,&nbsp;Xiqing Yan ,&nbsp;Chong Zhang ,&nbsp;Liqiang Wu","doi":"10.1016/j.ejmech.2024.117029","DOIUrl":"10.1016/j.ejmech.2024.117029","url":null,"abstract":"<div><div>The combined treatment with histone deacetylase (HDAC) inhibitors with peroxisome proliferator-activated receptor γ (PPARγ) agonists has displayed significant anticancer efficacy. Based on these results, a series of cloxiquine derivatives were prepared as potent HDAC inhibitors for the treatment of melanoma. Among these compounds, <strong>CS4</strong> exhibited excellent inhibitory effects on HDAC1 (IC₅₀ = 38 nM) and HDAC6 (IC₅₀ = 12 nM), and had good antiproliferative effects against A375 and SK-MEL-5 melanoma cells (IC₅₀ values, 1.20 and 0.93 μM, respectively). Mechanism research indicated that <strong>CS4</strong> inhibited SK-MEL-5 cell growth by promoting α-tubulin and histone 3 (H3) acetylation. At the metabolic level, treatment with <strong>BG11</strong> activated PPARγ and blocked glycolysis in SK-MEL-5 cells, which mediated partial antimelanoma effects of <strong>CS4</strong>. In addition, <strong>CS4</strong> also induced cell cycle arrest at G2, suppressed migration and facilitated apoptosis of SK-MEL-5 cells. More importantly, compound <strong>CS4</strong> demonstrated significant <em>in vivo</em> anticancer effect compared with SAHA, and exhibited neglectable toxicity. Consequently, <strong>CS4</strong> is the potent HDAC inhibitor, which may be developed as the candidate antimelanoma drug.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117029"},"PeriodicalIF":6.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580104","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}