journal
https://read.qxmd.com/read/38907990/biomimetic-analogues-of-the-desferrioxamine-e-siderophore-for-pet-imaging-of-invasive-aspergillosis-targeting-properties-and-species-specificity
#1
JOURNAL ARTICLE
Andrzej Mular, Isabella Hubmann, Milos Petrik, Katerina Bendova, Barbora Neuzilova, Mario Aguiar, Patricia Caballero, Abraham Shanzer, Henryk Kozłowski, Hubertus Haas, Clemens Decristoforo, Elzbieta Gumienna-Kontecka
The pathogenic fungus Aspergillus fumigatus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron from the host. Biomimetic FOXE analogues were labeled with gallium-68 for molecular imaging with PET. [68 Ga]Ga(III)-FOXE analogues were internalized in A. fumigatus cells via Sit1. Uptake of [68 Ga]Ga(III)-FOX 2-5, the most structurally alike analogue to FOXE, was high by both A. fumigatus and bacterial Staphylococcus aureus . However, altering the ring size provoked species-specific uptake between these two microbes: ring size shortening by one methylene unit (FOX 2-4) increased uptake by A...
June 22, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38907711/discovery-and-optimization-of-pyridazinones-as-pi3k%C3%AE-selective-inhibitors-for-administration-by-inhalation
#2
JOURNAL ARTICLE
Paolo Bruno, Alessandra Micoli, Mauro Corsi, Daniele Pala, Sara Guariento, Claudio Fiorelli, Paolo Ronchi, Alessandro Fioni, Paola Maria Gallo, Giulia Marenghi, Serena Bertolini, Silvia Capacchi, Valentina Mileo, Matteo Biagetti, Anna Maria Capelli
A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2 H )-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved...
June 22, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38906533/bifunctionality-and-antitumor-efficacy-of-zg-126-a-vitamin-d-receptor-agonist-histone-deacetylase-inhibitor-hybrid-molecule
#3
JOURNAL ARTICLE
Fatemeh Sarmadi, Zhizhong Gao, Jie Su, Camille Barbier, Patricio Artusa, Krikor Bijian, James L Gleason, John H White
Analogues of hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signal through the nuclear vitamin D receptor (VDR). They have potential in combination therapies with other anticancer agents such as histone deacetylase inhibitors (HDACi's). Here, we characterize the ZG series of hybrid compounds that combine HDACi within the backbone of a VDR agonist. All display improved solubility, with ZG-126 being the most robustly bifunctional molecule in multiple cell lines. ZG-126 is well tolerated and strongly induces VDR target gene expression in vivo at therapeutic doses...
June 21, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38905539/discovery-of-5-piperidin-4-yl-1-2-4-oxadiazole-derivatives-as-a-new-class-of-human-caseinolytic-protease-p-agonists-for-the-treatment-of-hepatocellular-carcinoma
#4
JOURNAL ARTICLE
Song Liu, Jing Sui, Baozhu Luo, Jiangnan Zhang, Xinrong Xiang, Tao Yang, Youfu Luo, Jie Liu
Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem . 2009, 7 (21), 4337-4348)...
June 21, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38905482/rational-molecular-editing-a-new-paradigm-in-drug-discovery
#5
EDITORIAL
Chunhua Ma, Craig W Lindsley, Junbiao Chang, Bin Yu
No abstract text is available yet for this article.
June 21, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38905437/dinuclear-tridentate-ru-ii-complex-with-strong-near-infrared-light-triggered-anticancer-activity
#6
JOURNAL ARTICLE
Li Wei, Rajesh Kushwaha, Tumpa Sadhukhan, Haorui Wu, Anyi Dao, Zhishang Zhang, Haotu Zhu, Qiufang Gong, Jiaxi Ru, Chao Liang, Pingyu Zhang, Samya Banerjee, Huaiyi Huang
The design of the dinuclear Ru(II) complex ( Ru2 ) with strong near-infrared (NIR) absorption properties has been reported for efficient anticancer phototherapy. Under 700 nm LED light excitation, Ru2 exhibited remarkable synergistic type I/II photosensitization ability and photocatalytic activity toward intracellular biomolecules. Ru2 showed impressive 700 nm light-triggered anticancer activity under normoxia and hypoxia compared with the clinically used photosensitizer Chlorin e6. The mechanistic studies showed that Ru2 induced intracellular redox imbalance and perturbed the energy metabolism and biosynthesis in A549 cancer cells...
June 21, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38900970/a-new-gramicidin-s-analogue-with-potent-antibacterial-activity-and-negligible-hemolytic-toxicity
#7
JOURNAL ARTICLE
John T Kalyvas, Yifei Wang, Luis Toronjo-Urquiza, Damian L Stachura, Jingxian Yu, John R Horsley, Andrew D Abell
Antibiotic resistance is an urgent threat to global health, with the decreasing efficacy of conventional drugs underscoring the urgency for innovative therapeutic strategies. Antimicrobial peptides present as promising alternatives to conventional antibiotics. Gramicidin S is one such naturally occurring antimicrobial peptide that is effective against Staphylococcus aureus , with a minimum inhibitory concentration (MIC) of 4 μg/mL (3.6 μM). Despite this potent activity, its significant hemolytic toxicity restricts its clinical use to topical applications...
June 20, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38897928/structure-based-design-and-synthesis-of-covalent-inhibitors-for-deubiquitinase-and-acetyltransferase-chladub1-of-chlamydia-trachomatis
#8
JOURNAL ARTICLE
Thomas Zimmermann, Jiachen Feng, Luana Janaína de Campos, Lindsey A Knight, Jan Schlötzer, Yesid A Ramirez, Kevin Schwickert, Markus Zehe, Thomas B Adler, Tanja Schirmeister, Caroline Kisker, Christoph Sotriffer, Martin Conda-Sheridan, Michael Decker
Upon infection by an intracellular pathogen, host cells activate apoptotic pathways to limit pathogen replication. Consequently, efficient proliferation of the obligate intracellular pathogen Chlamydia trachomatis , a major cause of trachoma and sexually transmitted diseases, depends on the suppression of host cell apoptosis. C. trachomatis secretes deubiquitinase ChlaDUB1 into the host cell, leading among other interactions to the stabilization of antiapoptotic proteins and, thus, suppression of host cell apoptosis...
June 19, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38896797/development-of-a-supermolecular-radionuclide-drug-conjugate-system-for-integrated-radiotheranostics-for-non-small-cell-lung-cancer
#9
JOURNAL ARTICLE
Xinmiao Lu, Yunyun Zhu, Xiaohui Deng, Fei Kong, Chuang Xi, Quanyong Luo, Xinyuan Zhu
Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131 I to construct the bulk of RDC (131 I-ER). Floxuridine was mixed with 131 I-ER to develop a hydrogen bond-driving supermolecular RDC system (131 I-ER-Fu NPs). The carrier-free 131 I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects...
June 19, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38896548/g-protein-coupled-estrogen-receptor-mediated-anti-inflammatory-and-mucosal-healing-activity-of-a-trimethylpyridinol-analogue-in-inflammatory-bowel-disease
#10
JOURNAL ARTICLE
Bhuwan Prasad Awasthi, Prakash Chaudhary, Dongchul Lim, Kiran Yadav, Iyn-Hyang Lee, Suhrid Banskota, Chhabi Lal Chaudhary, Ujjwala Karmacharya, Jiwoo Lee, So Myoung Im, YeonJu Nam, Ji Won Eun, Sungeun Lee, Ji-Min Lee, Eun Soo Kim, Chongsuk Ryou, Tae Hun Kim, Hee Dong Park, Jung-Ae Kim, Tae-Gyu Nam, Byeong-Seon Jeong
Inflammatory bowel disease (IBD) is characterized by abnormal immune responses, including elevated proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the gastrointestinal (GI) tract. This study presents the synthesis and anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues, which exhibit dual inhibition of TNFα- and IL-6-induced inflammation. Analysis using in silico methods, including 3D shape-based target identification, modeling, and docking, identified G protein-coupled estrogen receptor 1 (GPER) as the molecular target for the most effective analogue, 6 - 26 , which exhibits remarkable efficacy in ameliorating inflammation and restoring colonic mucosal integrity...
June 19, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38889244/discovery-of-jnj-74856665-a-novel-isoquinolinone-dhodh-inhibitor-for-the-treatment-of-aml
#11
JOURNAL ARTICLE
Lindsey G DeRatt, Zhuming Zhang, Christine Pietsch, Justin S Cisar, Xiaochun Zhang, Weixue Wang, Alexandra Tanner, Rosalie Matico, Paul Shaffer, Edgar Jacoby, Faraz Kazmi, Neetu Shukla, Tammy L Bush, Aaron Patrick, Ulrike Philippar, Ricardo Attar, James P Edwards, Scott D Kuduk
Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38889119/designing-chromane-derivatives-as-%C3%AE-2a-adrenoceptor-selective-agonists-via-conformation-constraint
#12
JOURNAL ARTICLE
Xucheng Lv, Peilan Zhou, Xuehong Qiao, Yulei Li, Xingxing Yang, Jiaqi Wang, Xinhua He, Ruibin Su
Enhancing the selectivity of alpha2 -adrenoceptor (α2A -AR) agonists remains an unresolved issue. Herein, we reported the design of an α2A -AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α2A -AR agonistic activity. Compounds A9 and B9 were identified as the most promising, exhibiting EC50 values of 0.78 and 0.23 nM, respectively...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38889052/discovery-of-novel-proteolysis-targeting-chimera-molecules-as-degraders-of-programmed-cell-death-ligand-1-for-breast-cancer-therapy
#13
JOURNAL ARTICLE
Hongjia Zhang, Yan Zhang, Zhanzhan Feng, Ming Shuai, Xinyu Ma, Shirui Wang, Su Yu, Rui Deng, Dan Luo, Jianyou Shi, Chunlan Pu, Rui Li
The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38888621/design-and-synthesis-of-clinical-candidate-pf-06852231-cvl-231-a-brain-penetrant-selective-positive-allosteric-modulator-of-the-m-4-muscarinic-acetylcholine-receptor
#14
JOURNAL ARTICLE
Christopher R Butler, Michael Popiolek, Laura A McAllister, Erik A LaChapelle, Melissa Kramer, Elizabeth M Beck, Scot Mente, Michael A Brodney, Matthew Brown, Adam Gilbert, Chris Helal, Kevin Ogilvie, Jeremy Starr, Daniel Uccello, Sarah Grimwood, Jeremy Edgerton, Jonathan Garst-Orozko, Rouba Kozak, Susan Lotarski, Amie Rossi, Deborah Smith, Rebecca O'Connor, John Lazzaro, Claire Steppan, Stefanus J Steyn
Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38888591/structural-optimization-of-marine-natural-product-pretrichodermamide-b-for-the-treatment-of-colon-cancer-by-targeting-the-jak-stat3-signaling-pathway
#15
JOURNAL ARTICLE
Yue Zhou, Na He, Qian Liu, Rui Li, Lujia Yang, Wei Kang, Xinxin Zhang, Xiaoyu Xu, Guangshan Yao, Pingyuan Wang, Chang-Yun Wang, Jinbo Yang, Zhiqing Liu
Marine natural product (MNP) pretrichodermamide B (Pre B, 9 ) was identified as a novel STAT3 inhibitor in our previous work, while its metabolic instability hindered its further development. To address this drawback, ligand structure-based drug design was adopted leading to a series of Pre B derivatives. Among them, MNP trichodermamide B (tri B, 24 ) obtained by skeletal rearrangement exhibited more potent antiproliferative activity with an IC50 value of 0.12 μM against HCT116. Notably, 24 stood out with improved metabolic stability ( T 1/2 = 31 min) and more favorable oral bioavailability ( F = 37...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38888292/design-synthesis-and-activity-evaluation-of-novel-benzazole-bifunctional-antifungal-inhibitors-with-an-ldh-carrier
#16
JOURNAL ARTICLE
Yating Liu, Shuai Yu, Yanqin He, Shiying Zhang, Min Liu, Jun Han, Bin Sun
Fungal infections maintain a close relation with the body's immune function. In this study, three series of benzazole compounds were designed as dual-target (PD-L1/CYP51) inhibitors using the skeleton splicing approach; their molecular structures were synthesized and evaluated accordingly. Among them, the compounds 9a-2 , 12a-2 , and 12b-1 exhibited potent antifungal activity and dual-target inhibition ability. Especially, the compound 12a-2 simultaneously exerted excellent bifunctional effects of fungal inhibition and immune activation...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38888140/discovery-of-a-novel-asm-direct-inhibitor-with-a-1-5-diphenyl-pyrazole-scaffold-and-its-antidepressant-mechanism-of-action
#17
JOURNAL ARTICLE
Shaochun Shi, Dingchen Ma, Ximing Guo, Yu Chen, Jinying Yu, Xiao Hu, Xuan Wang, Ting Li, Ke Wang, Yunbao Zhi, Guoqing Yang, Lizhi Lin, Qingjing Hao, Yuqiao Yang, Kan Yang, Jinxin Wang
Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great significance for exploring antidepressants and their mechanisms of action. Herein, a series of novel phenylpyrazole analogues were rationally designed and synthesized. Among them, compound 46 exhibited potent inhibitory activity (IC50 = 0.87 μM) and good drug-like properties. In vivo studies demonstrated that compound 46 was involved in multiple antidepressant mechanisms of action, which were associated with a decline of ceramide, including increasing the Bcl-2/Bax ratio and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating oxidative stress, reducing the levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, and elevating 5-HT levels in the brains of mice, respectively...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38888047/discovery-and-development-of-nlrp3-inhibitors-targeting-the-lrr-domain-to-disrupt-nlrp3-nek7-interaction-for-the-treatment-of-rheumatoid-arthritis
#18
JOURNAL ARTICLE
Bing-Yan Li, Pei Li, Lin-Yin Wei, Jia Zou, Yu-Hang Wang, Qi-Dong You, Cheng Jiang, Bin Di, Li-Li Xu
Rheumatoid arthritis (RA) is a chronic autoimmune disease. Targeting NLRP3 inflammasome, specifically its interaction with NEK7 via the LRR domain of NLRP3, is a promising therapeutic strategy. Our research aimed to disrupt this interaction by focusing on the LRR domain. Through virtual screening, we identified five compounds with potent anti-inflammatory effects and ideal LRR binding affinity. Lead compound C878-1943 underwent structural optimization, yielding pyridoimidazole derivatives with different anti-inflammatory activities...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38888038/discovery-of-a-double-stapled-short-peptide-as-a-long-acting-hiv-1-inactivator-with-potential-for-oral-bioavailability
#19
JOURNAL ARTICLE
Chao Wang, Wenpeng Zhang, Ling Xu, Jiahuang Tu, Shan Su, Qing Li, Tao Zhang, Longbo Zheng, Huan Wang, Xiaomei Zhuang, Xuan Tang, Yu Yuan, Guangpeng Meng, Lu Lu, Junhai Xiao, Qian Wang, Shibo Jiang
Different from most antiretroviral drugs that act as passive defenders to inhibit HIV-1 replication inside the host cell, virus inactivators can attack and inactivate HIV-1 virions without relying on their replication cycle. Herein, we describe the discovery of a hydrocarbon double-stapled helix peptide, termed D26. D26 is based on the HIV-1 gp41 protein lentiviral lytic peptide-3 motif (LLP3) sequence, which can efficiently inhibit HIV-1 infection and inactivate cell-free HIV-1 virions. It was noted that D26 was highly resistant to proteolytic degradation and exhibited a remarkably extended in vivo elimination half-life...
June 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38886162/design-synthesis-and-bioactivity-evaluation-of-a-tf-based-cancer-vaccine-candidate-using-lipid-a-mimetics-as-a-built-in-adjuvant
#20
JOURNAL ARTICLE
Lingqiang Gao, Guiqi Li, Cuiping Qiu, Yifan Ye, Xiaohui Li, Pan Liao, Wenbo Ming, Zhongqiu Liu, Xiang Luo, Guochao Liao
This study describes the design and synthesis of five TF-based cancer vaccine candidates using a lipid A mimetic as the carrier and a built-in adjuvant. All synthesized conjugates elicited robust and consistent TF-specific immune responses in mice without external adjuvants. Immunological studies subsequently conducted in wild-type and TLR4 knockout C57BL/6 mice demonstrated that the activation of TLR4 was the main reason that the synthesized lipid A mimetics increased the TF-specific immune responses. All antisera induced by these conjugates can specifically recognize, bind to, and induce the lysis of TF-positive cancer cells...
June 17, 2024: Journal of Medicinal Chemistry
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