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European Journal of Medicinal Chemistry

https://read.qxmd.com/read/38865743/a-chemical-modification-of-a-peroxisome-proliferator-activated-receptor-pan-agonist-produced-a-shift-to-a-new-dual-alpha-gamma-partial-agonist-endowed-with-mitochondrial-pyruvate-carrier-inhibition-and-antidiabetic-properties
#1
JOURNAL ARTICLE
Antonio Laghezza, Carmen Cerchia, Massimo Genovese, Roberta Montanari, Davide Capelli, Judith Wackerlig, Stefan Simic, Emanuele Falbo, Lucia Pecora, Rosalba Leuci, Leonardo Brunetti, Luca Piemontese, Paolo Tortorella, Abanish Biswas, Ravi Pratap Singh, Suhas Tambe, C A Sudeep, Ashok Kumar Pattnaik, Venkatesan Jayaprakash, Paolo Paoli, Antonio Lavecchia, Fulvio Loiodice
New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms...
June 9, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38865744/exploration-of-1-indolin-1-yl-2-thiazol-2-yl-ethan-1-one-derivatives-as-novel-anti-hbv-agent-with-potential-tlr7-agonistic-effect
#2
JOURNAL ARTICLE
Shuqiong Li, Lihua Yang, Qiuting Xu, Xincheng Li, Jiangyan Zhao, Zhoupeng Tan, Xiaoke Gu, Jingying Qiu
Hepatitis B virus (HBV) infection, as a serious global public health issue, is closely related to the immune dysfunction. Herein, thirty-seven 1-(indolin-1-yl)-2-(thiazol-4-yl)ethan-1-one derivatives were prepared as potential immunomodulatory anti-HBV agents. Anti-HBV activity evaluation confirmed compound 11a could significantly suppress the HBV DNA replication in both wild and resistant HBV stains, with IC50 values of 0.13 μM and 0.36 μM, respectively. Preliminary action mechanism studies showed that 11a had an inhibitory effect on cellular HBsAg secretion and could effectively activate TLR7, thereby inducing the secretion of TLR7-regulated cytokines IL-12, TNF-α and IFN-α in human PBMC cells...
June 8, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38861808/discovery-of-7-alkoxybenzofurans-as-pde4-inhibitors-with-hepatoprotective-activity-in-d-galn-lps-induced-hepatic-sepsis
#3
JOURNAL ARTICLE
Chuang Xia, Huizhen Wen, Lei Zheng, Yujie Ni, Huichang Bi, Haitao Wang, Jiangping Xu, Zhong-Zhen Zhou
Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor 4e, demonstrating better PDE4B (IC50  = 10.0 nM) and PDE4D (IC50  = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study...
June 7, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38861809/novel-hsp90-targeting-protacs-enhanced-synergy-with-cisplatin-in-combination-therapy-of-cervical-cancer
#4
JOURNAL ARTICLE
Jinsen Liang, Dandan Wang, Yijin Zhao, Yihe Wu, Xuelian Liu, Lilan Xin, Junhong Dai, Hang Ren, Hai-Bing Zhou, Hongbing Cai, Chune Dong
The development of effective drugs for cervical cancer is urgently required because of its high mortality rate and the limited treatment options. Herein, we report the design, synthesis, and evaluation of a series of novel and effective Hsp90-targeting PROTACs. These compounds exhibited potent anti-proliferative activity against cervical cancer cells with low IC50 values. Compound lw13 effectively degraded Hsp90 at a concentration of only 0.05 μM. In addition, it can inhibit the metastasis of cancer cells and induce significant cell cycle arrest and apoptosis...
June 6, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38857566/advances-in-dual-targeting-inhibitors-of-hdac6-for-cancer-treatment
#5
REVIEW
Zhicheng Gu, Shuxian Lin, Junhui Yu, Fei Jin, Qingqing Zhang, Keli Xia, Lei Chen, Yan Li, Bin He
Histone Deacetylase 6 (HDAC6) is an essential regulator of histone acetylation processes, exerting influence on a multitude of cellular functions such as cell motility, endocytosis, autophagy, apoptosis, and protein trafficking through its deacetylation activity. The significant implications of HDAC6 in diseases such as cancer, neurodegenerative disorders, and immune disorders have motivated extensive investigation into the development of specific inhibitors targeting this enzyme for therapeutic purposes. Single targeting drugs carry the risk of inducing drug resistance, thus prompting exploration of dual targeting therapy which offers the potential to impact multiple signaling pathways simultaneously, thereby lowering the likelihood of resistance development...
June 6, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38852337/new-insights-into-butyrylcholinesterase-pharmaceutical-applications-selective-inhibitors-and-multitarget-directed-ligands
#6
REVIEW
Tianyu Sun, Tengfei Zhen, Chrisanta Hamis Harakandi, Lei Wang, Huanchao Guo, Yao Chen, Haopeng Sun
Butyrylcholinesterase (BChE), also known as pseudocholinesterase and serum cholinesterase, is an isoenzyme of acetylcholinesterase (AChE). It mediates the degradation of acetylcholine, especially under pathological conditions. Proverbial pharmacological applications of BChE, its mutants and modulators consist of combating Alzheimer's disease (AD), influencing multiple sclerosis (MS), addressing cocaine addiction, detoxifying organophosphorus poisoning and reflecting the progression or prognosis of some diseases...
June 4, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38865742/small-molecule-inhibitors-targeting-heat-shock-protein-90-an-updated-review
#7
REVIEW
Yulong Li, Jinyun Dong, Jiang-Jiang Qin
As a molecular chaperone, heat shock protein 90 (HSP90) plays important roles in the folding, stabilization, activation, and degradation of over 500 client proteins, and is extensively involved in cell signaling, proliferation, and survival. Thus, it has emerged as an important target in a variety of diseases, including cancer, neurodegenerative diseases, and viral infections. Therefore, targeted inhibition of HSP90 provides a valuable and promising therapeutic strategy for the treatment of HSP90-related diseases...
June 3, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38850856/dpre1-and-ddn-as-promising-therapeutic-targets-in-the-development-of-novel-anti-tuberculosis-nitroaromatic-drugs
#8
JOURNAL ARTICLE
Romain Paoli-Lombardo, Nicolas Primas, Patrice Vanelle
Tuberculosis remains the second deadliest infectious disease in humans and a public health threat due to the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. Therefore, it is urgent to identify new anti-tuberculosis treatments and novel therapeutic targets to prevent the emergence of resistance. In recent years, the study of anti-tuberculosis properties of nitroaromatic compounds has led to the identification of two novel biological targets, the deazaflavin (F420 )-dependent nitroreductase Ddn and the decaprenylphosphoryl-β-d-ribose 2'-epimerase DprE1...
June 2, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38838545/discovery-of-novel-benzimidazole-derivatives-as-selective-and-reversible-monoamine-oxidase-b-inhibitors-for-parkinson-s-disease-treatment
#9
JOURNAL ARTICLE
Yangjing Lv, Miaoliang Fan, Jiayan He, Xiaoxin Song, Jianan Guo, Bianbian Gao, Jingqi Zhang, Changjun Zhang, YuanYuan Xie
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action...
June 2, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38850857/design-synthesis-biological-evaluation-and-in-silico-studies-of-novel-pyridopyridine-derivatives-as-anticancer-candidates-targeting-fms-kinase
#10
JOURNAL ARTICLE
Anusha Sebastian, Reinad R Abu Rabah, Seyed-Omar Zaraei, Srinivasulu Vunnam, Shaista Sultan, Hanan S Anbar, Randa El-Gamal, Hamadeh Tarazi, Nadin Sarg, Dima W Alhamad, Salma A Al Shamma, Afnan I Shahin, Hany A Omar, Taleb H Al-Tel, Mohammed I El-Gamal
Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce apoptosis and alter cell cycle progression in hepatocellular carcinoma cells...
June 1, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38843586/derivatives-of-d-glutamine-based-mmp-2-inhibitors-as-an-effective-remedy-for-the-management-of-chronic-myeloid-leukemia-part-i-synthesis-biological-screening-and-in-silico-binding-interaction-analysis
#11
JOURNAL ARTICLE
Sanjib Das, Subha Mondal, Tarun Patel, Ambati Himaja, Nilanjan Adhikari, Suvankar Banerjee, Sandip Kumar Baidya, Asit Kumar De, Shovanlal Gayen, Balaram Ghosh, Tarun Jha
Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML. In this article, some D(-)glutamine derivatives were synthesized and evaluated through cell-based antileukemic assays and tested against gelatinases...
June 1, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38852338/non-kinase-off-target-inhibitory-activities-of-clinically-relevant-kinase-inhibitors
#12
REVIEW
Nickolas R Brauer, Allison L Kempen, Delmis Hernandez, Herman O Sintim
Protein kinases are responsible for a myriad of cellular functions, such as cell cycle, apoptosis, and proliferation. Because of this, kinases make excellent targets for therapeutics. During the process to identify clinical kinase inhibitor candidates, kinase selectivity profiles of lead inhibitors are typically obtained. Such kinome selectivity screening could identify crucial kinase anti-targets that might contribute to drug toxicity and/or reveal additional kinase targets that potentially contribute to the efficacy of the compound via kinase polypharmacology...
May 31, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38851056/psammaplin-a-analogues-with-modified-disulfide-bond-targeting-histone-deacetylases-synthesis-and-biological-evaluation
#13
JOURNAL ARTICLE
Yukun Jiang, Ya Tang, Yuxuan Li, Lu Liu, Kairui Yue, Xiaoyang Li, Peiju Qiu, Ruijuan Yin, Tao Jiang
Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide marine metabolite, has been reported could inhibit HDAC1/2/3 through its thiol monomer. Inspired by the disuflide bond structure of this marine natural product, we designed and synthesized a series of PsA analogues, in which the disulfide bond of PsA was replaced with diselenide bond or cyclic disulfide/diselenide/selenenylsulfide motifs. We also studied the HDAC inhibition, cell growth inhibition, and apoptosis induction of these PsA analogues...
May 31, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38850855/development-of-novel-bisphenol-derivatives-with-a-membrane-targeting-mechanism-as-potent-gram-positive-antibacterial-agents
#14
JOURNAL ARTICLE
Rongcui Zhong, Zikai Xu, Shujun Zhang, Minghui Zeng, Haizhou Li, Shouping Liu, Shuimu Lin
Antibiotic resistance is becoming increasingly severe. The development of small molecular antimicrobial peptides is regarded as a promising design strategy for antibiotics. Here, a series of bisphenol derivatives with amphiphilic structures were designed and synthesized as antibacterial agents by imitating the design strategy of antimicrobial peptides. After a series of structural optimizations, lead compound 43 was identified, which exhibited excellent antibacterial activity against Gram-positive bacterial strains (MICs = 0...
May 31, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38838547/research-progress-on-gpx4-targeted-compounds
#15
REVIEW
Bingru Li, Keguang Cheng, Tzumei Wang, Xing Peng, Ping Xu, Guoquan Liu, Dong Xue, Ning Jiao, Chao Wang
Blocking the System Xc -_ GSH_ GPX4 pathway to induce ferroptosis in tumor cells is a novel strategy for cancer treatment. GPX4 serves as the core of the System Xc-/GSH/GPX4 pathway and is a predominant target for inducing ferroptosis in tumor cells. This article summarizes compounds identified in current research that directly target the GPX4 protein, including inhibitors, activators, small molecule degraders, chimeric degraders, and the application of combination therapies with other drugs, aiming to promote further research on the target and related diseases...
May 31, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38838546/poly-adp-ribose-polymerase-parp-inhibitors-as-anticancer-agents-an-outlook-on-clinical-progress-synthetic-strategies-biological-activity-and-structure-activity-relationship
#16
REVIEW
Pronoy Kanti Das, Gurubasavaraja Swamy Purawarga Matada, Rohit Pal, Lalmohan Maji, Prasad Sanjay Dhiwar, B V Manjushree, M P Viji
Poly (ADP-ribose) polymerase (PARP) is considered an essential component in case of DNA (Deoxyribonucleic acid) damage, response by sensing DNA damage and engaging DNA repair proteins. Those proteins repair the damaged DNA via an aspect of posttranslational modification, known as poly (ADP-Ribosyl)ation (PARylation). Specifically, PARP inhibitors (PARPi) have shown better results when administered alone in a variety of cancer types with BRCA (Breast Cancer gene) mutation. The clinical therapeutic benefits of PARP inhibitors have been diminished by their cytotoxicity, progression of drug resistance, and limitation of indication, regardless of their tremendous clinical effectiveness...
May 31, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38823265/dual-target-inhibitors-of-colchicine-binding-site-for-cancer-treatment
#17
REVIEW
Lu Lu, Keke Li, Jiaxin Pu, Shaochi Wang, Tingting Liang, Jianhong Wang
Colchicine binding site inhibitors (CBSIs) have attracted much attention due to their antitumor efficacies and the advantages of inhibiting angiogenesis and overcoming multidrug resistance. However, no CBSI has been currently approved for cancer treatment due to the insufficient efficacies, serious toxicities and poor pharmacokinetic properties. Design of dual-target inhibitors is becoming a potential strategy for cancer treatment to improve anticancer efficacy, decrease adverse events and overcome drug resistance...
May 31, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38852339/targeting-cyclin-dependent-kinases-from-pocket-specificity-to-drug-selectivity
#18
REVIEW
Yaoguang Huang, Wenwu Liu, Changhao Zhao, Xiaoyu Shi, Qingchun Zhao, Jingming Jia, Anhua Wang
The development of selective modulators of cyclin-dependent kinases (CDKs), a kinase family with numerous members and functional variations, is a significant preclinical challenge. Recent advancements in crystallography have revealed subtle differences in the highly conserved CDK pockets. Exploiting these differences has proven to be an effective strategy for achieving excellent drug selectivity. While previous reports briefly discussed the structural features that lead to selectivity in individual CDK members, attaining inhibitor selectivity requires consideration of not only the specific structures of the target CDK but also the features of off-target members...
May 29, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38823266/cyclodextrin-based-metal-organic-frameworks-transforming-drug-delivery
#19
REVIEW
Na Yang, Lingling Wei, Yuou Teng, Peng Yu, Cen Xiang, Jiang Liu
Cyclodextrin-based metal-organic frameworks (CD-MOFs) are gaining traction in the realm of drug delivery due to their inherent versatility and potential to amplify drug efficacy, specificity, and safety. This article explores the predominant preparation techniques for CD-MOFs, encompassing methods like vapor diffusion, microwave-assisted, and ultrasound hydrothermal approaches. Native CD-MOFs present compelling advantages in drug delivery applications. They can enhance drug loading capacity, stability, solubility, and bioavailability by engaging in diverse interactions with drugs, including host-guest, hydrogen bonding, and electrostatic interactions...
May 29, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38823263/synthesis-and-preclinical-evaluation-of-68-ga-labeled-psma-tracers-with-improved-pharmacological-properties
#20
JOURNAL ARTICLE
Haodong Hou, Yixiang Lin, Yuan Pan, Yuze Ma, Guihua Hou, Xiangyang Sun, Feng Gao
Prostate cancer (PCa) is one of the most common tumors in men, with the overexpression of prostate-specific membrane. In this study, we developed four new 68 Ga-labeled PSMA-targeting tracers by introducing quinoline, phenylalanine and decanoic acid groups to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Four radiotracers were synthesized with radiochemical purity >95 %, and exhibited high stability in vivo and in vitro. The inhibition constants (Ki ) of SDTWS01-04 to PSMA were in the nanomolar range (<10 nM)...
May 28, 2024: European Journal of Medicinal Chemistry
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