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Discovery of novel polyheterocyclic neuraminidase inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-12 Lin Lin Shang, Zhi Jian Zhong, Li Ping Cheng
Inspired by our earlier findings regarding neuraminidase (NA) inhibitors interacting with 150-cavity or 430-cavity of NA, sixteen novel polyheterocyclic NA inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone were designed and synthesized based on the lead compound . Of the synthesized compounds, compound targeting 150-cavity exerts the best inhibitory activity against the wild-type H5N1
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Insights from structure-activity relationships and the binding mode of peptidic α-ketoamide inhibitors of the malaria drug target subtilisin-like SUB1 Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-11 Alice Legru, Fernando A. Batista, Anna K. Puszko, Anthony Bouillon, Manon Maurel, Mariano Martinez, Abdelaziz Ejjoummany, Laura Ortega Varga, Pauline Adler, Ariel Méchaly, Margot Hadjadj, Piotr Sosnowski, Gérard Hopfgartner, Pedro M. Alzari, Arnaud Blondel, Ahmed Haouz, Jean-Christophe Barale, Jean-François Hernandez
multi-resistance, including against artemisinin, seriously threatens malaria treatment and control. Hence, new drugs are urgently needed, ideally targeting different parasitic stages, which are not yet targeted by current drugs. The SUB1 protease is involved in both hepatic and blood stages due to its essential role in the egress of parasites from host cells, and, as potential new target, it would
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Novel pyrrole based CB2 agonists: New insights on CB2 receptor role in regulating neurotransmitters' tone Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-11 Simone Di Micco, Tania Ciaglia, Emanuela Salviati, Perrone Michela, Magdalena Kostrzewa, Simona Musella, Aniello Schiano Moriello, Veronica Di Sarno, Gerardina Smaldone, Francesca Di Matteo, Ilaria Capolupo, Rosmara Infantino, Giuseppe Bifulco, Giacomo Pepe, Eduardo M. Sommella, Poulami Kumar, Manuela Giovanna Basilicata, Marco Allarà, Nuria Sánchez-Fernández, Ester Aso, Isabel M. Gomez-Monterrey,
The cannabinoid system is one of the most investigated neuromodulatory systems because of its involvement in multiple pathologies such as cancer, inflammation, and psychiatric diseases. Recently, the CB2 receptor has gained increased attention considering its crucial role in modulating neuroinflammation in several pathological conditions like neurodegenerative diseases. Here we describe the rational
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Scaffold hopping derived novel benzoxazepinone receptor-interacting protein kinase 1 (RIP1) inhibitors as anti-necroptosis agents: Anti-inflammatory effect in systemic inflammatory response syndrome (SIRS) and epilepsy Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-09 Ruiqi Jiang, Bin Xu, Shumeng Zhi, Lei Sun, Baocong Yu, Qing Huang, Ying Shi
Necroptosis is a type of regulated cell death known for its pro-inflammatory nature due to the substantial release of cellular contents. The phosphorylation of key proteins, namely RIP1, RIP3, and mixed lineage kinase domain-like protein (MLKL), plays a pivotal role in the processes associated with necroptosis. Consequently, inhibiting the phosphorylation of any of these three key protein kinases could
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Improving Anti-HIV activity and pharmacokinetics of enfuvirtide (T20) by modification with oligomannose Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-08 Shuihong Cheng, Mingyue Xu, Mingli Li, Yong Feng, Lin He, Tong Liu, Liying Ma, Xuebing Li
Dendritic cells (DCs) play a pivotal role in controlling HIV-1 infections of CD4 T cells. DC-SIGN, which is expressed on the surface of DCs, efficiently captures HIV-1 virions by binding to the highly mannosylated membrane protein, gp120, and then the DCs transport the virus to target T cells in lymphoid organs. This study explored the modification of T20, a peptide inhibitor of HIV-1 fusion, by conjugation
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Ligand-based design and synthesis of new trityl histamine and trityl cysteamine derivatives as SIRT2 inhibitors for cancer therapy Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-07 Mostafa M. Badran, Samar H. Abbas, Hiroshi Tateishi, Yuki Maemoto, Tsugumasa Toma, Akihiro Ito, Mikako Fujita, Masami Otsuka, Mohamed Abdel-Aziz, Mohamed O. Radwan
The relentless pursuit of novel therapeutic agents against cancer has led to the identification of multiple molecular targets, among which Sirtuin 2 (SIRT2) has garnered significant attention. This study presents an extensive SAR study of our reported trityl scaffold-based SIRT2 inhibitors. This study encompasses a range of different medicinal chemistry approaches to improve the activity of the lead
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Discovery of novel peptide–dehydroepiandrosterone hybrids inducing endoplasmic reticulum stress with effective in vitro and in vivo anti-melanoma activities Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-07 Juan Feng, Yidong Liu, Xia Tian, Chen Shen, Zhiqiang Feng, Jingxu Zhang, Xiangli Yao, Meilin Pu, Xuguang Miao, Lan Ma, Shouxin Liu
Steroid hybrids have emerged as a type of advantageous compound as they could offer improved pharmacological and pharmaceutical properties. Here, we report a series of novel peptide–dehydroepiandrosterone hybrids, which would effectively induce endoplasmic reticulum stress (ERS) and lead to apoptosis with outstanding and anti-melanoma effects. The lead compound among various steroids conjugated with
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Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-07 Scott H. Henderson, Fiona J. Sorrell, James M. Bennett, Oleg Fedorov, Marcus T. Hanley, Paulo H. Godoi, Roberta Ruela de Sousa, Sean Robinson, Iva Hopkins Navratilova, Jonathan M. Elkins, Simon E. Ward
Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-]pyridazine through structure−activity relationship exploration and drug design efforts led to the discovery of as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of was elucidated with X-ray crystallography
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Structure-based approaches for the design of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazoles as tubulin polymerization inhibitors Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-06 Mingxin Huang, Hongyao Han, Haoyuan Liu, Runlai Liu, Jiwei Li, Mi Li, Qi Guan, Weige Zhang, Dun Wang
The colchicine binding site on tubulin has been widely acknowledged as an attractive target for anticancer drug exploitation. Here, we reported the structural optimization of the lead compound , which was proved in our previous work as a colchicine binding site inhibitor (CBSI). Based on docking researches for the active binding conformation of compound , a series of novel 6-aryl-1-(3,4,5-trimetho
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Discovery of 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-05 Xiaorong Qiu, Rong Liu, Huan Ling, Yang Zhou, Xiaomei Ren, Fengtao Zhou, Jinwei Zhang, Weixue Huang, Zhen Wang, Ke Ding
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling. While HPK1 is considered as a promising target for cancer immunotherapy, no small-molecule HPK1 inhibitors have been approved for cancer treatment. Herein, we report the discovery of a series of new HPK1 inhibitors with a 5-aminopyrido[2,3-]pyrimidin-7(8)-one scaffold. The most potent compound inhibited HPK1
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Sulfone-based human liver pyruvate kinase inhibitors – Design, synthesis and in vitro bioactivity Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-05 Josipa Matić, Fady Akladios, Umberto Maria Battisti, Liliana Håversen, Amalyn Nain-Perez, Anders Foller Füchtbauer, Woonghee Kim, Leticia Monjas, Alexandra Rodriguez Rivero, Jan Borén, Adil Mardinoglu, Mathias Uhlen, Morten Grøtli
Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have
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A first-in-class β-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-05 Vasilii F. Otvagin, Lubov V. Krylova, Nina N. Peskova, Natalia S. Kuzmina, Ekaterina A. Fedotova, Alexander V. Nyuchev, Yuliya V. Romanenko, Oscar I. Koifman, Sergey Z. Vatsadze, Hans-Günther Schmalz, Irina V. Balalaeva, Alexey Yu Fedorov
In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin- photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced
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Synthesis and preliminary anticancer evaluation of photo-responsive prodrugs of hydroxymethylene bisphosphonate alendronate Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-05 Aurélie Descamps, Philippe Arnoux, Céline Frochot, Florent Barbault, Julia Deschamp, Maelle Monteil, Evelyne Migianu-Griffoni, Thibaut Legigan, Marc Lecouvey
The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their short plasmatic half-life which preclude their accumulation in non-skeletal tumors. In this context, the use of lipophilic prodrugs represents a simple and straightforward strategy to enhance the biodistribution of bisphosphonates
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Biochemical and structural characterization of chlorhexidine as an ATP-assisted inhibitor against type 1 methionyl-tRNA synthetase from Gram-positive bacteria Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-04 Feihu Lu, Kaijiang Xia, Jingtian Su, Jia Yi, Zhiteng Luo, Jun Xu, Qiong Gu, Bingyi Chen, Huihao Zhou
Methionyl-tRNA synthetase (MetRS) catalyzes the attachment of l-methionine (l-Met) to tRNA to generate methionyl-tRNA, an essential substrate for protein translation within ribosome. Owing to its indispensable biological function and the structural discrepancies with human counterpart, bacterial MetRS is considered an ideal target for developing antibacterials. Herein, chlorhexidine (CHX) was identified
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Structure-based discovery of potent CARM1 inhibitors for colorectal cancer therapy Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-04 Chenyu Liu, Yang Li, Zhihao Liu, Chenxi Cao, Min Lin, Xin Chen, Mengting Yuan, Yaohua Fan, Xiaodong Gu, Lei Wang, Fan Yang, Fei Ye, Jia Jin
Coactivator-associated arginine methyltransferase 1 (CARM1) plays an important role in cell proliferation and gene expression, and is highly expressed in a variety of tumor tissues. Guided by our previous reported structure of DCPR049_12, we focused on designing and evaluating selective CARM1 inhibitors, resulting in the identification of compound as a promising lead candidate. Compound displayed potent
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Design and biological evaluation of dual tubulin/HDAC inhibitors based on millepachine for treatment of prostate cancer Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-03 Shanshan Xie, Jiafu Leng, Shifang Zhao, Liqiao Zhu, Mengyu Zhang, Mengdan Ning, Bo Zhao, Lingyi Kong, Yong Yin
In this work, a novel of dual tubulin/HDAC inhibitors were designed and synthesized based on the structure of natural product millepachine, which has been identified as a tubulin polymerization inhibitor. Biological evaluation revealed that compound exhibited an impressive potency against PC-3 cells with the IC value of 16 nM and effectively inhibited both microtubule polymerization and HDAC activity
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Discovery of 2,9-diaryl-6-carbamoylpurines as a novel class of antitubercular agents Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-02 Carla Correia, Ana Claúdia Leite, Alexandra G. Fraga, M. Fernanda Proença, Jorge Pedrosa, M. Alice Carvalho
A series of novel 9-alkyl/aryl-2-aryl-6-carbamoylpurines were synthesized, and their activity against strain HRv was assessed. The SAR analysis on the first set of derivatives, with an alkyl or aryl unit at N-9 and a phenolic unit at C-2, showed that the activity depends on the purine ring substituents at N-9 and C-2. A phenyl group at N-9 combined with a 3-hydroxyphenyl or 4-hydroxyphenyl at C-2 improve
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Advances in molecular agents targeting toll-like receptor 4 signaling pathways for potential treatment of sepsis Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-02 Yunyun Zheng, Yingying Gao, Weiru Zhu, Xian-guang Bai, Jinxu Qi
Sepsis is a systemic inflammatory response syndrome caused by an infection. Toll-like receptor 4 (TLR4) is activated by endogenous molecules released by injured or necrotic tissues. Additionally, TLR4 is remarkably sensitive to infection of various bacteria and can rapidly stimulate host defense responses. The TLR4 signaling pathway plays an important role in sepsis by activating the inflammatory response
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Optimizing drug-like properties of selective butyrylcholinesterase inhibitors for cognitive improvement: Enhancing aqueous solubility by disrupting molecular plane Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-02 Shuaishuai Xing, Xu Tang, Leyan wang, Jun Wang, Bingbing Lv, Xiaolong Wang, Can Guo, Ye Zhao, Feng Feng, Wenyuan Liu, Yao Chen, Haopeng Sun
Most recently, worldwide interest in butyrylcholinesterase (BChE) as a potential target for treating Alzheimer's disease (AD) has increased. In this study, the previously obtained selective BChE inhibitors with benzimidazole-oxadiazole scaffold were further structurally modified to increase their aqueous solubility and pharmacokinetic (PK) characteristics. – showed improved solubility (3280 μM, upgraded
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Design, synthesis and antibacterial evaluation of low toxicity amphiphilic-cephalosporin derivatives Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-03-01 Shengcong Chen, Shangshang Qin, Ruirui Li, Ye Qu, Maxwell Ampomah-Wireko, Lauraine Nininahazwe, Meng Wang, Chen Gao, En Zhang
Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length
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Synthesis and mitochondria-localized iridium (III) complexes induce cell death through pyroptosis and ferroptosis pathways Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-29 Huiyan Hu, Fan Zhang, Zhujun Sheng, Shuang Tian, Gechang Li, Shuanghui Tang, Yajie Niu, Jiawan Yang, Yunjun Liu
This paper introduces a new ligand, 4,6-dichloro-5-(1-imidazo [4,5-f]phenanthroline-2-yl)pyrimidin-2-amine (DPPA), and its corresponding new iridium(III) complexes: [Ir(ppy)(DPPA)](PF) (2a) (where ppy represents deprotonated 2-phenylpyridine), [Ir(bzq)(DPPA)](PF) (2b) (with bzq indicating deprotonated benzo[h]quinoline), and [Ir(piq)(DPPA)](PF) (2c) (piq denoting deprotonated 1-phenylisoquinoline)
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Discovery of anti-inflammatory agents from 3, 4-dihydronaphthalene-1(2H)-one derivatives by inhibiting NLRP3 inflammasome activation Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-29 Wen-Xuan Li, Lu Yu, Jiang-Bo Chi, Ji-Peng Wang, Yong-Jun Liu, Chun-Hua Wang, Meng Zhang, Gui-Ge Hou
NLRP3 inflammatory vesicles are a polymer of cellular innate immunity composed of a pair of proteins. The continuous activation of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammatory vesicles induces the occurrence and enhancement of inflammatory response. In this study, a series of 3, 4-dihydronaphthalene-1(2)-one derivatives (DHNs, , , ) were synthesized and characterized by
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Targeting kelch-like (KLHL) proteins: Achievements, challenges and perspectives Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-29 Yangguo Zhou, Qiong Zhang, Ziquan Zhao, Xiuqi Hu, Qidong You, Zhengyu Jiang
Kelch-like proteins (KLHLs) are a large family of BTB-containing proteins. KLHLs function as the substrate adaptor of Cullin 3-RING ligases (CRL3) to recognize substrates. KLHLs play pivotal roles in regulating various physiological and pathological processes by modulating the ubiquitination of their respective substrates. Mounting evidence indicates that mutations or abnormal expression of KLHLs are
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Novel thiazolidin-4-one benzenesulfonamide hybrids as PPARγ agonists: Design, synthesis and in vivo anti-diabetic evaluation Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-29 Islam H. Ali, Rasha M. Hassan, Ahmed M. El Kerdawy, Mahmoud T. Abo-Elfadl, Heba M.I. Abdallah, Francesca Sciandra, Iman A.Y. Ghannam
In the current study, two series of novel thiazolidin-4-one benzenesulfonamide arylidene hybrids and were designed, synthesized and tested for their PPARɣ agonistic activity. The phenethyl thiazolidin-4-one sulphonamide showed the highest PPARɣ activation % by 41.7%. Whereas, the 3-methoxy- and 4-methyl-4-benzyloxy thiazolidin-4-one sulphonamides , and revealed moderate PPARɣ activation % of 31.7,
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Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4 Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-28 Xiaojuan Chen, Huiliang Li, Qianmeng Lin, Shuyan Dai, Lingzhi Qu, Ming Guo, Lin Zhang, Jiaxuan Liao, Hudie Wei, Guangyu Xu, Longying Jiang, Yongheng Chen
Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4
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The mechanism of UNC-51-like kinase 1 and the applications of small molecule modulators in cancer treatment Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-28 Dejuan Sun, Zhiqi Zhang, Xinbo Yu, Hua Li, Xiaobo Wang, Lixia Chen
Autophagy is a process of self-renewal in cells, which not only provides the necessary nutrients for cells, but also clears necrotic organelles. Autophagy disorders are closely related to diseases such as cancer. UNC-51-like kinase 1 (ULK1) is a serine/threonine protein kinase that plays a crucial role in receiving input from energy and nutrient sensors, activating autophagy to maintain cellular homeostasis
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Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-28 Huijuan Song, Shangze Yang, Shuo Wu, Xiaoyu Qin, Ya Wang, Xican Ma, Jiaqi Gong, Meng Wei, Apeng Wang, Mengyuan Wang, Kun Lan, Juan Guo, Mingliang Liu, Xingjuan Chen, Yuhuan Li, Kai Lv
The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both and . However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating
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Insight into small-molecule inhibitors targeting extracellular nucleotide pyrophosphatase/phosphodiesterase1 for potential multiple human diseases Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-27 Baochan Du, Jinxiao Ru, Zixuan Zhan, Congcong Lin, Yang Liu, Wuyu Mao, Jifa Zhang
Extracellular nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as a type II transmembrane glycoprotein. It plays a crucial role in various biological processes, such as bone mineralization, cancer cell proliferation, and immune regulation. Consequently, ENPP1 has garnered attention as a promising target for pharmacological interventions. Despite its potential, the development
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Hit-to-lead optimization of 2-aminoquinazolines as anti-microbial agents against Leishmania donovani Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-27 Nirmal Das, Jayasree Roy, Binita Patra, Eleanor Saunders, Dipika Sarkar, Sunny Goon, Bishnu Prasad Sinha, Shreya Roy, Swarnali Roy, Jafar Sarif, Purbita Bandopadhyay, Subhasis Barik, Suravi Mukherjee, Nicole McNamara, Swapna Varghese, Kaylene Simpson, Jonathan Baell, Malcolm McConville, Dipyaman Ganguly, Arindam Talukdar
Visceral leishmaniasis is a potentially fatal disease caused by infection by the intracellular protist pathogens or . Present therapies are ineffective because of high costs, variable efficacy against different species, the requirement for hospitalization, toxicity and drug resistance. Detailed analysis of previously published hit molecules suggested a crucial role of ‘guanidine’ linkage for their
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Research progress on asialoglycoprotein receptor-targeted radiotracers designed for hepatic nuclear medicine imaging Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-27 Yuqi Hua, Chunjing Yu
Asialoglycoprotein receptor (ASGPR) specifically recognizes glycans terminated with β--galactose or -acetylgalactosamine. Its exclusive expression in mammalian hepatocytes renders it an ideal hepatic-targeted biomarker. To date, ASGPR-targeted ligands have been actively developed for drug delivery and hepatic imaging. This review provides a comprehensive summary of the progress achieved to-date in
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Structure-based design and synthesis of BML284 derivatives: A novel class of colchicine-site noncovalent tubulin degradation agents Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-27 Chufeng Zhang, Wei Yan, Yan Liu, Minghai Tang, Yaxin Teng, Fang Wang, Xiuying Hu, Min Zhao, Jianhong Yang, Yong Li
Our previous studies have demonstrated that BML284 is a colchicine-site tubulin degradation agent. To improve its antiproliferative properties, 45 derivatives or analogs of BML284 were designed and synthesized based on the cocrystal structure of BML284 and tubulin. Among them, was the most potent derivative, with IC values ranging from 0.02 to 0.05 μM against the five tested tumor cell lines. Structure–activity
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Research progress of DDR1 inhibitors in the treatment of multiple human diseases Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-27 Mengying Liu, Jifa Zhang, Xiaoxue Li, Yuxi Wang
Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic
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Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-26 Qingjing Hao, Junwei Shi, Zhilan Zhang, Guoqing Yang, Yunbao Zhi, Ke Wang, Dingchen Ma, Shengnan Fu, Haijuan Dong, Zhuoer Zhi, Wenting Zhang, Tingting Li, Jinxin Wang
Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol lipase (MAGL), an essential enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), is a novel target for developing antidepressants. A decrease of 2-AG levels in the hippocampus of the brain has been observed in depressive-like models induced by chronic stress. Herein, employing a structure-based
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Current advances and development strategies of targeting son of sevenless 1 (SOS1) in drug discovery Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-25 Jialin Wu, Xiaoxue Li, Chengyong Wu, Yuxi Wang, Jifa Zhang
The Son of Sevenless 1 (SOS1) guanine nucleotide exchange factor, prevalent across eukaryotic species, plays a pivotal role in facilitating the attachment of RAS protein to GTP, thereby regulating the activation of intracellular RAS proteins. This regulation is part of a feedback mechanism involving SOS1, which allows both activators and inhibitors of SOS1 to exert control over downstream signaling
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Small-molecule agents for treating skin diseases Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-24 Hong Cai, Hao Wen, Junjie Li, Liuxin Lu, Wenxuan Zhao, Xiaoying Jiang, Renren Bai
Skin diseases are a class of common and frequently occurring diseases that significantly impact daily lives. Currently, the limited effective therapeutic drugs are far from meeting the clinical needs; most drugs typically only provide symptomatic relief rather than a cure. Developing small-molecule drugs with improved efficacy holds paramount importance for treating skin diseases. This review aimed
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Discovery of novel urea derivatives as ferroptosis and autophagy inducer for human colon cancer treatment Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-24 Tingting Liang, Haiyang Dong, Zhuangzhuang Wang, Lu Lu, Xueting Song, Jianguo Qi, Yahong Zhang, Jianhong Wang, Guanhua Du
A series of novel urea derivatives were designed, synthesized and evaluated for their inhibitory activities against HT-29 cells, and structure-activity relationships (SAR) were summarized. Compound stood out from these derivatives, exhibiting the most potent antiproliferative activity. Further biological studies demonstrated that arrested cell cycle at G2/M phase via regulating cell cycle-related proteins
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Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-24 Yaxin Teng, Rui Wu, Weichen Bo, Minghai Tang, TaiJin Wang, Xue Cui, Yong Li, Chufeng Zhang, Ziyan Ma, Zhiyuan Fu, Qing Xu, Jie Liu, Lijuan Chen
Traf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/-catenin pathway and is considered an important target for the treatment of colorectal cancer. Inhibiting TNIK has potential to block abnormal Wnt/-catenin signal transduction caused by colorectal cancer mutations. We discovered a series of 6-(1-methyl-1-imidazole-5-yl) quinoline derivatives
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Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-24 Franck Amblard, Julia C. LeCher, Ramyani De, Shaoman Zhou, Peng Liu, Shu Ling Goh, Sijia Tao, Dharmeshkumar Patel, Jessica Downs-Bowen, Keivan Zandi, Huanchun Zhang, Gitika Chaudhry, Tamara McBrayer, Michael Muczynski, Abdullah Al-Homoudi, Joseph Engel, Shuiyun Lan, Stefan G. Sarafianos, Ladislau C. Kovari, Raymond F. Schinazi
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and related variants, are responsible for the devastating coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 main protease (Mpro) plays a central role in the replication of the virus and represents an attractive drug target. Herein, we report the discovery of novel SARS-CoV-2 Mpro covalent inhibitors, including highly effective
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The discovery of potent USP2/USP8 dual-target inhibitors for the treatment of breast cancer via structure guided optimization of ML364 Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-24 Yucheng Tian, Kang Liu, Dongdong Wu, Liuyi Wu, Qianqian Xu, Wei Wei, Zhiyu Li, Qianming Du, Jinlei Bian
USP2 and USP8 are crucial in the development and progression of breast cancer, primarily through the stabilization of protein substrates such as Her2 and ERα. The dual-target inhibitor , targeting both USP2 and USP8, has garnered significant interest in recent research. In this study, we developed a series of derivatives using ligand-based drug design strategies. The standout compound, , demonstrated
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Structure modification of anoplin for fighting resistant bacteria Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-24 Chao Zhong, Jing Zou, Wenbo Mao, Ping Yang, Jingying Zhang, Sanhu Gou, Yun Zhang, Hui Liu, Jingman Ni
The emergence of bacterial resistance has posed a significant challenge to clinical antimicrobial treatment, rendering commonly used antibiotics ineffective. The development of novel antimicrobial agents and strategies is imperative for the treatment of resistant bacterial infections. Antimicrobial peptides (AMPs) are considered a promising class of antimicrobial agents due to their low propensity
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Recent advances and mechanisms of action of PD-L1 degraders as potential therapeutic agents Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-23 Feng Zhang, Ruiya Jiang, Shishi Sun, Caiyun Wu, Qimeng Yu, Annoor Awadasseid, Jianwei Wang, Wen Zhang
PD-L1 is an important immune checkpoint protein that can bind to T cells' PD-1 receptor, thereby promoting immune escape from tumors. In recent years, many researchers have developed strategies to degrade PD-L1 to improve the effect of immunotherapy. The study of degrading PD-L1 provides new opportunities for immunotherapy. Here, we mainly summarize and review the current active molecules and mechanisms
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A conjugate vaccine strategy that induces protective immunity against arecoline Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-23 Xu-Guang Yin, Xiang-Zhao Chen, Jia-Ling Qiu, Zhi-Kai Yu, li-Yuan Chen, Si-Qi Huang, Wen-Na Huang, Xiang Luo, Ke-Wu Zhu
Betel-quid chewing addiction is the leading cause of oral submucous fibrosis and oral cancer, resulting in significant socio-economic burdens. Vaccination may serve as a promising potential remedy to mitigate the abuse and combat accidental overdose of betel nut. Hapten design is the crucial factor to the development of arecoline vaccine that determines the efficacy of a candidate vaccine. Herein,
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Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-23 Shiyi Yin, Mengmeng Shen, Yongjiang Zhang, Jiannan Wu, Run Song, Xiaoyi Lai, Zhenzhen Tian, Tingting Wang, Weina Jin, Junqiang Yan
Parkinson's disease (PD) is characterized by the progressive death of dopamine (DA) neurons and the pathological accumulation of α-synuclein (α-syn) fibrils. In our previous study, simulated PHB2 phosphorylation was utilized to clarify the regulatory role of c-Abl in PHB2-mediated mitophagy in PD models. In this investigation, we employed an independently patented PHB2Y121 phosphorylated antibody in
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Unlocking the potential of 1,4-naphthoquinones: A comprehensive review of their anticancer properties Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-23 Eduardo Angulo-Elizari, Andreina Henriquez-Figuereo, Cristina Morán-Serradilla, Daniel Plano, Carmen Sanmartín
Cancer encompasses a group of pathologies with common characteristics, high incidence, and prevalence in all countries. Although there are treatments available for this disease, they are not always effective or safe, often failing to achieve the desired results. This is why it is necessary to continue the search for new therapies. One of the strategies for obtaining new antitumor drugs is the use of
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Novel strategies based on natural products and synthetic derivatives to overcome resistance in Mycobacterium tuberculosis Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-23 Adelina-Gabriela Niculescu, Georgiana Ramona Mük, Speranta Avram, Ilinca Margareta Vlad, Carmen Limban, Diana Nuta, Alexandru Mihai Grumezescu, Mariana-Carmen Chifiriuc
One of the biggest health challenges of today's world is the emergence of antimicrobial resistance (AMR), which renders conventional therapeutics insufficient and urgently demands the generation of novel antimicrobial strategies. (), the pathogen causing tuberculosis (TB), is among the most successful bacteria producing drug-resistant infections. The versatility of allows it to evade traditional anti-TB
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Discovery of novel osthole derivatives exerting anti-inflammatory effect on DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-22 Ying Zhou, Zhiteng Du, Qianqian Wu, Mi Guo, Zhichao Chen, Chenhui Sun, Xiaobo Li, Yu Zou, Zhiwei Zheng, Pan Chen, Won-Jea Cho, Young-Chang Cho, Nipon Chattipakorn, Yi Wang, Guang Liang, Qidong Tang
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Comprehensive review on the elaboration of payloads derived from natural products for antibody-drug conjugates Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-22 Nan Lu, Jiaqi Wu, Mengwei Tian, Shanshan Zhang, Zhiguo Li, Liming Shi
Antibody-drug conjugates (ADCs) have arisen as a promising class of biotherapeutics for targeted cancer treatment, combining the specificity of monoclonal antibodies with the cytotoxicity of small-molecule drugs. The choice of an appropriate payload is crucial for the success development of ADCs, as it determines the therapeutic efficacy and safety profile. This review focuses on payloads derived from
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Novel membrane-targeting isoxanthohumol-amine conjugates for combating methicillin-resistant Staphylococcus aureus (MRSA) infections Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-21 Ruige Yang, Wanqing Cheng, Meijuan Huang, Ting Xu, Miaomiao Zhang, Jifeng Liu, Shangshang Qin, Yong Guo
Methicillin-resistant (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Here, a series of novel isoxanthohumol-amine conjugates were synthesized as antibacterials. After bioactivity evaluation, a compound was obtained, which showed excellent antibacterial activity against and
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Identification of a ferritinophagy inducer via sinomenine modification for the treatment of colorectal cancer Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-21 Ling Zhu, Chen Chen, Yuxing Cai, Yalin Li, Lijie Gong, Tianyu Zhu, Lingyi Kong, Jianguang Luo
Ferritinophagy is a cellular process to release redox-active iron. Excessive activation of ferritinophagy ultimately results in ferroptosis characterized by ROS accumulation which plays important roles in the development and progression of cancer. Sinomenine, a main bioactive alkaloid from the traditional Chinese medicine , inhibits the proliferation of cancer cells by promoting ROS production. Herein
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Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-20 Lianhua Piao, Ying Gao, Xiaoshuang Xu, Yangyang Su, Yanong Daniel Wang, Jie Zhou, Yang Gao, Jin Fang, Qihui Li, Shan Chang, Ren Kong
Nuclear receptor binding SET domain (NSD) proteins are a class of histone lysine methyltransferases and implicated in multiple cancer types with aberrant expression and involvement of cancer related signaling pathways. In this study, a series of small-molecule compounds including compound and are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound
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Targeting bromodomian-containing protein 8 (BRD8): An advanced tool to interrogate BRD8 Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-20 Tingting Wu, Yali Chen, Qidong You, Zhengyu Jiang, Xuetao Chen
Epigenetic modifications play crucial roles in physiological processes, including cell differentiation, proliferation, and death. Bromodomain/Brd-containing proteins (BCPs) regulate abnormal gene expression in various diseases by recognizing the lysine-ε-N-acetylated residues (KAc) or by acting as transcriptional co-activators. Small molecule inhibitors targeting BCPs offer an attractive strategy for
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Total synthesis and structural modification of the dibenzylbutane lignan LCA as a potent anti-inflammatory agent against LPS-induced acute lung injury Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-20 Juan Zhang, Zhen Wang, Jing Wang, Xiaobin Zhuo, Luyao Yu, Ting Han, Yan Song, Conghao Gai, Yan Zou, Qingguo Meng, Xiaoyun Chai, Qingjie Zhao
Acute lung injury (ALI) is a serious public health problem associated with high morbidity and mortality. However, few efficacious drugs are clinically available. Inhibition of proinflammatory cytokines is considered to be a promising method for the treatment of inflammatory diseases. Herein, the total synthesis of a dibenzylbutane lignan, 9′--di-(E)-feruloyl--5,5′-dimethoxysecoisolariciresinol (LCA)
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Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-20 Jihyun Baek, Hyejin Kim, Joonhong Jun, Dahyun Kang, Hyunah Bae, Hyunwook Cho, Jung-Mi Hah
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Deep learning for advancing peptide drug development: Tools and methods in structure prediction and design Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-19 Xinyi Wu, Huitian Lin, Renren Bai, Hongliang Duan
Peptides can bind challenging disease targets with high affinity and specificity, offering enormous opportunities for addressing unmet medical needs. However, peptides’ unique features, including smaller size, increased structural flexibility, and limited data availability, pose additional challenges to the design process compared to proteins. This review explores the dynamic field of peptide therapeutics
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Structural modification based on the diclofenac scaffold: Achieving reduced colitis side effects through COX-2/NLRP3 selective inhibition Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-17 Zhiran Ju, Junde Xu, Keshuang Tang, Fener Chen
COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles -, triazoles -, and cyclic imides and , were synthesized. The synthesized analogues were evaluated for their inhibitory activity against
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Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells Eur. J. Med. Chem. (IF 6.7) Pub Date : 2024-02-17 Sama W.A. Helmy, Amal Kamal Abdel-Aziz, Eman M.E. Dokla, Tarek E. Ahmed, Yasmin Hatem, Engy A. Abdel Rahman, Marwa Sharaky, Mai I. Shahin, Eman Z. Elrazaz, Rabah A.T. Serya, Maged Henary, Sameh S. Ali, Dalal A. Abou El Ella
Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options targeted therapy. Beside kinases’ aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach