European Journal of Medicinal Chemistry最新文献

{"title":"Photosensitizer associated with efflux pump inhibitors as a strategy for Photodynamic Therapy against bacterial resistance","authors":"Ieda Vieira da Cunha, Douglas Davison da Silva Oliveira, Gabriel Guimarães Calefi, Nagela Bernadelli Sousa Silva, Carlos Henrique Gomes Martins, Celso de Oliveira Rezende Júnior, Tayana Mazin Tsubone","doi":"10.1016/j.ejmech.2024.117197","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117197","url":null,"abstract":"Antimicrobial resistance is currently one of the biggest challenges in controlling infectious diseases and was listed among the top 10 threats to global health by the World Health Organization (WHO) in 2023. The antibiotics misuse has led to the widespread emergence of antimicrobial resistance, marking the beginning of the alarming increase in antibiotic resistance. In this context, Antimicrobial Photodynamic Therapy (aPDT) has garnered significant attention from the scientific community due to its potential to effectively eliminate multidrug-resistant pathogenic bacteria and its low propensity to induce drug resistance, which bacteria can quickly develop against traditional antibiotic treatments. However, some efflux pumps can expel diverse substrates from inside the cell, including photosensitizers used in aPDT, contributing to multidrug-resistance mechanisms. Efflux Pump Inhibitors are potential solutions to combat resistance mediated by these pumps and can play a crucial role in enhancing aPDT's effectiveness against multidrug-resistant bacteria. Therefore, combining efflux pumps inhibitors with photosensitizers can possible to eliminate the pathogen more efficiently. This review summarizes the mechanisms in which bacteria resist conventional antibiotic treatment, with a particular emphasis on efflux pump-mediated resistance, and present aPDT as a promising strategy to combat antibiotic resistance. Additionally, we highlighted several molecules of photosensitizer associated with efflux pump inhibitors as potential strategies to optimize aPDT, aiming to offer a perspective on future research directions on aPDT for overcoming the limitations of antibiotic resistance.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869975","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":"The polypharmacy combination of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor gilteritinib (GIL) is more active in acute myeloid leukemia cells than novel polypharmacologic BCL-2/FLT3 VEN–GIL hybrid single-molecule inhibitors.","authors":"Christopher C. Goodis, Christian Eberly, Alexandria M. Chan, MinJung Kim, Brandon D. Lowe, Curt I. Civin, Steven Fletcher","doi":"10.1016/j.ejmech.2024.117190","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117190","url":null,"abstract":"Current treatments for acute myeloid leukemias (AMLs) cure fewer than 30% of patients. This low efficacy is due, in part, to the inter-patient and intra-patient heterogeneity of AMLs; accordingly, all current AML treatment regimens involve drug combinations (polypharmacy). A recently-completed clinical trial in relapsed/refractory AML using a combination of two newer targeted antileukemics, the BCL-2 inhibitor venetoclax (VEN) plus the FLT3 inhibitor gilteritinib (GIL), yielded highly promising results for this two-drug polypharmacy combination. Polypharmacology – wherein a single drug molecule that inhibits two or more biological targets is created – has been proposed to offer superior therapeutic results, as compared to the corresponding polypharmacy approach. Herein, we designed and synthesized several polypharmacologic dual BCL-2/FLT3 hybrid single-molecule inhibitors by tethering VEN to GIL, through their solvent-exposed domains. While the in vitro antileukemic activity of the two-drug VEN + GIL polypharmacy combination proved superior to our focused library of VEN-GIL hybrids, alternative grafting points on GIL may yield improved results for future hybrid compounds.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"83 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869974","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":"Developing Dual-Responsive Quinolinium Prodrugs of 8-Hydroxyquinoline By Harnessing the Dual Chelating Sites","authors":"Xueyan Yao, Junjiao Wang, Jie Liu, Chunjing Yu, Jing Hu, Xue Wang, Junjie Fu, Jian Yin","doi":"10.1016/j.ejmech.2024.117196","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117196","url":null,"abstract":"The bidentate metal ion chelator 8-hydroxyquinoline (8-HQ) demonstrates significant potential in anticancer therapy but is hindered by adverse effects due to nonspecific chelation in normal tissues. The phenolic hydroxyl oxygen of 8-HQ has been extensively exploited to develop <em>O</em>-masked 8-HQ prodrugs aimed at achieving on-demand chelation. However, the equally crucial quinoline nitrogen for chelation remains underutilized. By alkylating the quinoline nitrogen of 8-HQ, we synthesized a series of <em>N</em>-masked quinolinium (QUM) prodrugs that release 8-HQ upon activation by various stimuli. Comprehensive <em>in vitro</em> and <em>in vivo</em> studies were conducted with QUM-1 and QUM-4, which are activated by H₂O₂ and β-glucosidase, respectively. Both QUM-1 and QUM-4 exhibit improved cancer cell selectivity compared to 8-HQ or the <em>O</em>-masked isomeric prodrug, attributed to unique properties such as enhanced mitochondrial targeting and increased glucose transporter-mediated cellular uptake. Additionally, by leveraging both chelating sites, we constructed dual-masked 8-HQ prodrugs that are activated non-sequentially by two stimuli to release 8-HQ. QUM-5 demonstrates anticancer activity upon activation by UV/H₂O₂ and shows improved safety in mice compared to 8-HQ. Our research presents novel applications for the construction of quaternary ammonium prodrugs utilizing aromatic tertiary amines and underscores the potential of dual-responsive prochelators for targeted cancer therapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867497","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 Series of 3-Pyridyl-1,3-Thiazoles: In Vitro and In Vivo Anti-Trypanosomatidae Profile, in vitro and in silico Mechanism of Action approach","authors":"Vanessa Gouveia de Melo Silva, Lucas Manoel da Silva Sousa, Expedito Lopes Fernandes Junior, Graziella Leite Brondani, Isabeli Maria de Albuquerque Oliveira, Danilo Cesar Galindo Bedor, Isabella Barbosa Pereira Lopes, Fabio André Brayner, Luiz Carlos Alves, Marton Kaique de Andrade Cavalcante, Daniele Santana de Souza Oliveira, Maria Carolina Accioly Brelaz-de-Castro, Policarpo Ademar Sales Junior, Valéria Rêgo Alves Pereira, Ana Cristina Lima Leite","doi":"10.1016/j.ejmech.2024.117191","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117191","url":null,"abstract":"<em>Trypanosomatidae</em> diseases, such as Chagas disease and leishmaniasis, are caused by protozoan parasites of the <em>Trypanosomatidae</em> family, namely <em>Trypanosoma cruzi</em> and <em>Leishmania</em> species, respectively. There is an urgent need for new therapies. Both pyridine and thiazole rings are recognized as important scaffolds in medicinal chemistry. This study reports the synthesis of 3-pyridyl-1,3-thiazole derivatives (<strong>1–18</strong>) and their evaluation through <em>in vitro</em> and <em>in vivo</em> assays. <em>In vitro</em> tests were conducted against <em>T. cruzi</em>, <em>L. amazonensis</em>, and <em>L. infantum</em>, with cytotoxicity assessed using L929 fibroblasts and RAW 264.7 macrophages. Mode of action studies included <em>in vitro</em> assays and <em>in silico</em> simulations. Fourteen compounds exhibited trypanocidal activity with IC₅₀ values ranging from 0.2 to 3.9 μM, outperforming benznidazole (4.2 μM). Compound <strong>7</strong> displayed an IC₅₀ of 0.4 μM and a selectivity index of 530.8. However, the compounds were inactive in <em>in vivo</em> assays at a dose of 100 mg/kg/day. Compounds <strong>1</strong>, <strong>7</strong>, <strong>8</strong>, and <strong>10</strong> demonstrated trypanostatic effects, mitochondrial disruption, apoptosis induction, and parasite membrane damage. These compounds also modulated nitric oxide, IL-6, IL-10 and TNF production. <em>In silico</em> analysis indicated strong interactions with cruzain and favorable bioavailability, drug-likeness, and stability profiles. The leishmanicidal activity was negligible or absent. Despite promising <em>in vitro</em> trypanocidal activity, further structural optimization or formulation strategies are required to enhance oral stability and bioavailability, providing a foundation for the development of new therapeutic agents.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"79 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858181","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":"Dodecyl creatine ester, a promising treatment to deliver creatine to neurons, achieves pharmacology efficacy in creatine transporter deficiency","authors":"Clémence Disdier, Clara Lhotellier, Anne-Cécile Guyot, Narciso Costa, Frédéric Théodoro, Alain Pruvost, Matthew R. Skelton, Thomas Joudinaud, Aloïse Mabondzo, Henri Bénech","doi":"10.1016/j.ejmech.2024.117195","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117195","url":null,"abstract":"Dodecyl creatine ester (DCE) is a creatine prodrug currently developed for brain diseases, including creatine transporter deficiency (CTD), an incurable rare genetic disease. A dual strategy combining a prodrug to bypass the non-functional creatine transporter and its delivery via the nose-to-brain pathway has been proposed to replenish creatine levels in cerebral cells, particularly in neurons of CTD patients. <em>In vitro</em> and <em>in vivo</em> studies in various animal models, including wild-type non-human primates and creatine transporter deficient mice, show that formulated DCE, when administered intranasally, achieves significant cerebral distribution up to the target cells, the neurons, and modulates the expression of neuronal markers related to cognitive function at doses intended for patients.These compelling results contribute to a better understanding of the pharmacokinetics and pharmacodynamics of DCE after nasal administration, with a particular focus on the crucial role of the nose-to-brain pathway in DCE distribution.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"63 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Clinical Application of New Drugs Approved by NMPA in 2023","authors":"Lijuan Xie, Yingying Wang, Kunyu Wang, Wanying Chen, Fuwei Yang","doi":"10.1016/j.ejmech.2024.117181","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117181","url":null,"abstract":"The National Medical Products Administration (NMPA) in China plays a crucial role in regulating drug approval and ensuring the safety and efficacy of pharmaceutical products. In 2023, the NMPA authorized the approval of 82 novel therapeutic agents, including 48 chemical drugs, 22 biological drugs, 4 vaccines, and 8 traditional Chinese medicines. These approvals span a broad spectrum of therapeutic areas, with a strong focus on oncology, central nervous system disorders, anti-infective treatments, hematology, cardiovascular diseases, ophthalmology, and immunomodulation. The review discusses the synthetic routes and clinical application of representative 36 new drugs, offering insights into the design, development, and optimization of these drugs. Our objective is to inspire innovation and contribute to the establishment of novel, efficient, and scalable synthetic approaches, thereby advancing the frontiers of pharmaceutical research and development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858184","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":"Synthetic Approaches and Clinical Applications of Representative HDAC Inhibitors for Cancer Therapy: A Review","authors":"Zhengming Lv, Tianyi Ji, Jie Liu, Xu Sun, Huimin Liang","doi":"10.1016/j.ejmech.2024.117185","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117185","url":null,"abstract":"Histone deacetylase (HDAC) inhibitors are a promising class of epigenetic modulators in cancer therapy. This review provides a comprehensive analysis of recent synthetic strategies and clinical applications of key HDAC inhibitors for oncology. HDACs play a critical role in modulating chromatin structure and gene expression by removing acetyl groups from histone proteins, leading to transcriptional repression of tumor suppressor genes. By inhibiting HDAC activity, HDAC inhibitors restore normal acetylation patterns, reactivating silenced tumor suppressor genes and inducing cell cycle arrest, apoptosis, and autophagy in cancer cells. The review explores synthetic approaches to developing representative HDAC inhibitors that have been approved or in various clinical trials. Through an integrated perspective on the synthesis, mechanism of action, and clinical advancements of HDAC inhibitors, this review aims to guide future research toward next-generation HDAC inhibitors that could enhance cancer treatment efficacy while minimizing toxicity, offering insights for chemists and clinicians in the field of oncology.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858058","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 and optimization of 1,2,4-triazole derivatives as novel ferroptosis inhibitors","authors":"Jiawei Zhang, Fang Lin, Yijie Xiao, Si-Yu Cen, Bi-Wen Wan, Xuan Li, Yahui Zhao, Yi He, Hai-Xin Yuan, Shenyou Nie","doi":"10.1016/j.ejmech.2024.117192","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117192","url":null,"abstract":"Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid ROS accumulation, which is associated with various diseases, including acute organ injury, neurodegenerative disorders, and cancer. Pharmacological inhibition of ferroptosis has great potential for the treatment of these diseases. However, the clinical translation of many ferroptosis inhibitors is hindered by their inadequate activity or suboptimal pharmacokinetic profiles. In this study, several 1,2,4-triazole derivatives were identified as novel ferroptosis inhibitors through phenotypic screening of our in-house compound library. Among these compounds, <strong>NY-26</strong> was found to significantly inhibit RSL3-induced ferroptosis in 786-O cells with nanomolar level (EC₅₀ = 62 nM). The antiferroptotic activity of <strong>NY-26</strong> was further validated across multiple cell lines. Mechanistic studies revealed that <strong>NY-26</strong> inhibits ferroptosis through its intrinsic free radical-trapping antioxidant capacity. Additional results demonstrated that the triazole derivatives could effectively ameliorate ferroptosis-related pathological conditions in a mouse model of ConA-induced acute liver injury. Taken together, <strong>NY-26</strong>, tethering a novel 1,2,4-triazole scaffold, could be an effective ferroptosis inhibitor with great therapeutic potential for further investigation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858183","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 Selective c-MET Kinase Inhibitors: Application of Fused [5,6]-Bicyclic Nitrogen-Containing Cores for Anticancer Drug Design","authors":"Mehdi Valipour, Zahra Zakeri khatir, Adileh Ayati, Asieh Hosseini, Mohammad Sheibani, Hamid Irannejad","doi":"10.1016/j.ejmech.2024.117177","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117177","url":null,"abstract":"Over the past two decades, small molecules bearing [5,6]-bicyclic nitrogen-containing cores have emerged as one of the most extensively studied structures for the development of selective c-MET kinase inhibitors. Structure-activity relationship (SAR) studies have demonstrated that modifying these cores can significantly impact the biological properties of c-MET inhibitors, including safety/toxicity, potency, and metabolic stability. For example, although c-MET kinase inhibitors containing the [1,2,4]triazolo[4,3-b][1,2,4]triazine scaffold (core <strong>P</strong>) exhibit high inhibitory potency, they often face challenges due to metabolic stability defects. Alternatively, compounds containing [1,2,3]triazolo[4,5-b]pyrazine (core <strong>K</strong>) and [1,2,4]triazolo[4,3-b]pyridazine (core <strong>I</strong>) scaffolds demonstrate lower potency but improved metabolic stability, allowing some of them to progress into clinical trials and even be approved as novel anticancer drugs. Fortunately, X-ray crystallography studies have well elucidated key interactions between [5,6]-bicyclic nitrogen-containing cores and crucial amino acid residues within the c-MET active site. These insights emphasize the significance of π-π stacking interactions with Tyr1230 and hydrogen bonding with Asp1222, providing valuable guidance for the targeted design and optimization of selective c-MET kinase inhibitors. Following the identification/introduction of sixteen distinct [5,6]-bicyclic nitrogen-containing cores (cores <strong>A-P</strong>) utilized in the design of selective c-MET kinase inhibitors over the past two decades, this manuscript offers a comprehensive review of their roles in drug development of anticancer agents, and describes the various synthesis methods employed. The insights presented herein can serve as a resource for better structural optimization of c-MET kinase inhibitors in the future research.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"97 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858187","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":"Benzimidazole analogues active against adult Schistosoma mansoni: SAR analyses, In vivo efficacy in mice, and preliminary mechanistic studies as potential inhibitors of hemozoin formation","authors":"Godwin A. Dziwornu, Henrietta Dede Attram, Cécile Haberli, Keabetswe Masike, Mathew Njoroge, Jennifer Keiser","doi":"10.1016/j.ejmech.2024.117186","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117186","url":null,"abstract":"For over three decades, praziquantel (PZQ) has been the mainstay chemotherapy for prevention and treatment of schistosomiasis. The excessive use of PZQ, coupled with the lack of advanced drug candidates in the current anti-schistosomiasis drug development pipeline, emphasizes the genuine need for new drugs. In the current work, we investigated the antischistosomal potential of a new series of compounds derived from the privileged benzimidazole scaffold, which exhibited low micromolar IC₅₀ potency in the range of 1.0 – 2.7 μM against S. mansoni adult worms, in vitro. However, representative compounds showed low in vivo activity. One compound (15) reduced worm burden by 51.9% but not significant. Furthermore, by invoking inhibition of hemozoin formation, an immutable drug target in Schistosoma adult worms, as a likely contributing mode of action, we observed that the most potent analogues were equally potent inhibitors of β-hematin (synthetic hemozoin) formation in a cell-free assay.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858182","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}