Design, synthesis, and biological evaluation of novel double-winged galloyl derivatives as HIV-1 RNase H inhibitors
In this report, we report on a series of II-25 derivatives, obtained by addition of different hydrophobic moieties ("the wings") at the C-2 and C-3 positions of the piperazine ring that showed improved RNase H inhibitory activity. Six compounds showed strong inhibitory activity and were found to be more potent than β-thujaplicinol in enzymatic assays. The most potent compound was IA-6 and exhibited the best inhibitory activity (IC50 = 0.067 ± 0.02 μM). IA-6 was around 11 and 30 times more potent than II-25 and β-thujaplicinol, respectively. Molecular modeling studies predict a strong hydrophobic interaction between the...
Source: European Journal of Medicinal Chemistry - July 3, 2022 Category: Chemistry Authors: Lina Zhang Fenju Wei David Borrego Fabao Zhao Javier Mart ínez Del Río Estrella Frutos-Beltr án Jiwei Zhang Shujing Xu Nerea L ópez-Carrobles Shenghua Gao Dongwei Kang Christophe Pannecouque Erik De Clercq Xinyong Liu Luis Men éndez-Arias Peng Zhan Source Type: research

Design, synthesis, and biological evaluation of novel double-winged galloyl derivatives as HIV-1 RNase H inhibitors
In this report, we report on a series of II-25 derivatives, obtained by addition of different hydrophobic moieties ("the wings") at the C-2 and C-3 positions of the piperazine ring that showed improved RNase H inhibitory activity. Six compounds showed strong inhibitory activity and were found to be more potent than β-thujaplicinol in enzymatic assays. The most potent compound was IA-6 and exhibited the best inhibitory activity (IC50 = 0.067 ± 0.02 μM). IA-6 was around 11 and 30 times more potent than II-25 and β-thujaplicinol, respectively. Molecular modeling studies predict a strong hydrophobic interaction between the...
Source: European Journal of Medicinal Chemistry - July 3, 2022 Category: Chemistry Authors: Lina Zhang Fenju Wei David Borrego Fabao Zhao Javier Mart ínez Del Río Estrella Frutos-Beltr án Jiwei Zhang Shujing Xu Nerea L ópez-Carrobles Shenghua Gao Dongwei Kang Christophe Pannecouque Erik De Clercq Xinyong Liu Luis Men éndez-Arias Peng Zhan Source Type: research

Complete regression of xenografted breast tumors by dextran-based dual drug conjugates containing paclitaxel and docosahexaenoic acid
This study revealed that the dextran-based dual drug conjugates may represent an effective and innovative way to deliver anticancer agents to a variety of tumors.PMID:35779290 | DOI:10.1016/j.ejmech.2022.114567 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - July 2, 2022 Category: Chemistry Authors: Shenxu Wang Jiaojiao Liu Hongshuai Lv Xiaoyan Huang Peng Dong Qi Wang Haotong Yang Si Wang Xiaohai Li Jinghua Hu Dandan Wang Shengnan Cao Liangyu Xie Yikang Shi Source Type: research

A multi-pronged evaluation of aldehyde-based tripeptidyl main protease inhibitors as SARS-CoV-2 antivirals
Eur J Med Chem. 2022 Jun 27;240:114570. doi: 10.1016/j.ejmech.2022.114570. Online ahead of print.ABSTRACTAs an essential enzyme of SARS-CoV-2, the COVID-19 pathogen, main protease (MPro) is a viable target to develop antivirals for the treatment of COVID-19. By varying chemical compositions at both P2 and P3 positions and the N-terminal protection group, we synthesized 18 tripeptidyl MPro inhibitors that contained also an aldehyde warhead and β-(S-2-oxopyrrolidin-3-yl)-alaninal at the P1 position. Systematic characterizations of these inhibitors were conducted, including their in vitro enzymatic inhibition potency, X-ray ...
Source: European Journal of Medicinal Chemistry - July 2, 2022 Category: Chemistry Authors: Yuying Ma Kai S Yang Zhi Zachary Geng Yugendar R Alugubelli Namir Shaabani Erol C Vatansever Xinyu R Ma Chia-Chuan Cho Kaustav Khatua Jing Xiao Lauren R Blankenship Ge Yu Banumathi Sankaran Pingwei Li Robert Allen Henry Ji Shiqing Xu Wenshe Ray Liu Source Type: research

Discovery of dual inhibitors of topoisomerase I and Cyclooxygenase-2 for colon cancer therapy
Eur J Med Chem. 2022 Jun 23;240:114560. doi: 10.1016/j.ejmech.2022.114560. Online ahead of print.ABSTRACTNovel tolfenamic acid derivatives based on the structure of I-1 were designed and synthesized to improve its poor target inhibition and solubility. Among them, W10 was identified as a potent dual-target inhibitor of Topo I (IC50 = 0.90 ± 0.17 μM) and COX-2 (IC50 = 2.31 ± 0.07 μM) with improved water solubility (32.33 μg/mL). Moreover, W10 also exhibited fairly potent anti-proliferative and pro-apoptosis activity via the mitochondrial pathway, as well as suppressed aberrant NF-κB/IκB activation in colon cancer cel...
Source: European Journal of Medicinal Chemistry - July 1, 2022 Category: Chemistry Authors: Xiaoling Hu Junfang Li Honghua Zhang Quanwei Yu Yuying Wang Xuelin Li Lin Long Weifan Jiang Zhen Wang Source Type: research

Design, synthesis, and evaluation of aryl-thioether ruthenium polypyridine complexes: A multi-target antimicrobial agents against gram-positive bacteria
In this study, four new ruthenium polypyridine complexes bearing 4-tBu-phenyl sulfide Ru(bpy)2(TBPIP)](PF6)2(Ru(Ⅱ)-1), Ru(dmb)2(TBPIP)](PF6)2(Ru(Ⅱ)-2), Ru(dmob)2(TBPIP)](PF6)2(Ru(Ⅱ)-3) and Ru(dtb)2(TBPIP)](PF6)2(Ru(Ⅱ)-4) were designed, synthesized and evaluated. Those ruthenium complexes showed strong activity against Staphylococcus aureus (S. aureus) in vitro and in vivo. The Ru(Ⅱ)-1 showed excellent antimicrobial activity against Gram-positive bacteria (MIC = 2.0 μg/mL), poor hemolytic activity (HC50 > 200 μg/mL), and low cytotoxicity to mammalian cells. Ru(Ⅱ)-1 can kill bacteria quickly by destroying th...
Source: European Journal of Medicinal Chemistry - July 1, 2022 Category: Chemistry Authors: Zhang ChunYan Yu RuJian Wang LiQiang Huang HaiYan Wang JinTao Liao XiangWen Duan XueMin Xiong YanShi Source Type: research

Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties
Eur J Med Chem. 2022 Jun 3;239:114507. doi: 10.1016/j.ejmech.2022.114507. Online ahead of print.ABSTRACTThe absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug...
Source: European Journal of Medicinal Chemistry - June 30, 2022 Category: Chemistry Authors: Joana Reis Carlos Fernandes Hoda Salem Marta Maia Cl áudia Tomé Sofia Benfeito Jos é Teixeira Paulo J Oliveira Eugenio Uriarte Francesco Ortuso Stefano Alcaro Donatella Bagetta Fernando Cagide Fernanda Borges Source Type: research

Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties
Eur J Med Chem. 2022 Jun 3;239:114507. doi: 10.1016/j.ejmech.2022.114507. Online ahead of print.ABSTRACTThe absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug...
Source: European Journal of Medicinal Chemistry - June 30, 2022 Category: Chemistry Authors: Joana Reis Carlos Fernandes Hoda Salem Marta Maia Cl áudia Tomé Sofia Benfeito Jos é Teixeira Paulo J Oliveira Eugenio Uriarte Francesco Ortuso Stefano Alcaro Donatella Bagetta Fernando Cagide Fernanda Borges Source Type: research

Computational method for the systematic alignment of analogue series with structure-activity relationship transfer potential across different targets
Eur J Med Chem. 2022 Jun 23;239:114558. doi: 10.1016/j.ejmech.2022.114558. Online ahead of print.ABSTRACTLead optimization focuses on the generation of analogue series (ASs) with sustainable structure-activity relationship (SAR) progression. If roadblocks are encountered during multi-property optimization, it is often desirable to replace an AS with another containing a different core structure but having similar SAR characteristics for a given target. This process represents target-based SAR transfer. A previously unexplored question is to what extent AS-based SAR transfer events might also occur across different targets....
Source: European Journal of Medicinal Chemistry - June 28, 2022 Category: Chemistry Authors: Atsushi Yoshimori J ürgen Bajorath Source Type: research

Log P analyzation-based discovery of GSH activated biotin-tagged fluorescence probe for selective colorectal cancer imaging
In this study, F1 was found as an effective targeted activatable fluorescent probe based on log P analysis. In vitro experiments demonstrated that the initial fluorescence of the developed probe F1 was initially well quenched, and the fluorescence increased after the probe interacted with glutathione. Cell imaging results showed that the probe had good cell permeability and selectivity. Remarkably, F1 displayed enhanced tumor tissue fluorescence in MC-38 tumor-bearing mice. Notably, it showed selectivity in imaging clinical specimens of human colorectal cancer tissues. Accordingly, this study shows that log P analysis can ...
Source: European Journal of Medicinal Chemistry - June 28, 2022 Category: Chemistry Authors: Jialiang Lu Qianqian Wang Zhaojun Wang Jinguo Liu Yu Guo Chenghao Pan Xin Li Jinxin Che Zheng Shi Shuo Zhang Source Type: research

Design, synthesis and biological evaluation of biphenyl-benzamides as potent FtsZ inhibitors
In this study, a series of novel biphenyl-benzamides as FtsZ inhibitors has been rationally designed, synthesized and evaluated for their antibacterial activities against various Gram-positive bacteria strains. In particular, the most promising compound 30 exhibited excellent antibacterial activities, especially against four different Bacillus subtilis strains, with an MIC range of 0.008 μg/mL to 0.063 μg/mL. Moreover, compound 30 also showed good pharmaceutical properties with low cytotoxicity (CC50 > 20 μg/mL), excellent human metabolic stability (T1/2 = 111.98 min), moderate pharmacokinetics (T1/2 = 2.26 h, F = 61...
Source: European Journal of Medicinal Chemistry - June 28, 2022 Category: Chemistry Authors: Jingjing Deng Tao Zhang Baiqing Li Mingyuan Xu Yuanze Wang Source Type: research

Identification of (S)-1-(2-(2,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea as a potential anti-colorectal cancer agent
Eur J Med Chem. 2022 Jun 22;239:114561. doi: 10.1016/j.ejmech.2022.114561. Online ahead of print.ABSTRACTIn our previous study, 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea (1) was obtained as a potent tyrosine kinase inhibitor. Further structural optimization was performed in this investigation, and a series of novel quinoline derivates were designed, synthesized and evaluated for their biological activity. Among them, compound 8m possessed nanomolar c-Met and Ron inhibitory activity, with IC50 values of 4.32 nM and 2.39 nM...
Source: European Journal of Medicinal Chemistry - June 28, 2022 Category: Chemistry Authors: Baohui Qi Fei Wang Huan He Mengmeng Fan Liping Hu Li Xiong Guowei Gong Shengmin Shi Xiaomeng Song Source Type: research

Synthesis and anti-trypanosomal evaluation of novel N-branched acyclic nucleoside phosphonates bearing 7-aryl-7-deazapurine nucleobase
Eur J Med Chem. 2022 Jun 23;239:114559. doi: 10.1016/j.ejmech.2022.114559. Online ahead of print.ABSTRACTA series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with Ki values of 1.7-14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma...
Source: European Journal of Medicinal Chemistry - June 28, 2022 Category: Chemistry Authors: Karol ína Vaňková Eva Dole želová Eva Tlou šťová Dana Hockov á Alena Z íková Zlatko Janeba Source Type: research

Computational method for the systematic alignment of analogue series with structure-activity relationship transfer potential across different targets
Eur J Med Chem. 2022 Jun 23;239:114558. doi: 10.1016/j.ejmech.2022.114558. Online ahead of print.ABSTRACTLead optimization focuses on the generation of analogue series (ASs) with sustainable structure-activity relationship (SAR) progression. If roadblocks are encountered during multi-property optimization, it is often desirable to replace an AS with another containing a different core structure but having similar SAR characteristics for a given target. This process represents target-based SAR transfer. A previously unexplored question is to what extent AS-based SAR transfer events might also occur across different targets....
Source: European Journal of Medicinal Chemistry - June 28, 2022 Category: Chemistry Authors: Atsushi Yoshimori J ürgen Bajorath Source Type: research

Log P analyzation-based discovery of GSH activated biotin-tagged fluorescence probe for selective colorectal cancer imaging
In this study, F1 was found as an effective targeted activatable fluorescent probe based on log P analysis. In vitro experiments demonstrated that the initial fluorescence of the developed probe F1 was initially well quenched, and the fluorescence increased after the probe interacted with glutathione. Cell imaging results showed that the probe had good cell permeability and selectivity. Remarkably, F1 displayed enhanced tumor tissue fluorescence in MC-38 tumor-bearing mice. Notably, it showed selectivity in imaging clinical specimens of human colorectal cancer tissues. Accordingly, this study shows that log P analysis can ...
Source: European Journal of Medicinal Chemistry - June 28, 2022 Category: Chemistry Authors: Jialiang Lu Qianqian Wang Zhaojun Wang Jinguo Liu Yu Guo Chenghao Pan Xin Li Jinxin Che Zheng Shi Shuo Zhang Source Type: research