Synthesis and structure-activity relationship study of novel 3-diethoxyphosphorylfuroquinoline-4,9-diones with potent antitumor efficacy
Eur J Med Chem. 2021 Apr 3;219:113429. doi: 10.1016/j.ejmech.2021.113429. Online ahead of print.ABSTRACTHerein we report an efficient synthesis of a series of regioisomeric N,O-syn and N,O-anti 3-diethoxyphosphorylfuroquinoline-4,9-diones combining furoquinoline-5,8-dione skeleton, present in several highly cytotoxic compounds, with diethoxyphosphoryl moiety. The cytotoxic activity of the obtained analogs was tested against two human cancer cell lines: promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7 and for comparison on human umbilical vein endothelial cells HUVEC and mammary gland/breast MCF-10 A cell...
Source: European Journal of Medicinal Chemistry - April 14, 2021 Category: Chemistry Authors: Jakub Modranka Joanna Drogosz-Stachowicz Anna Pietrzak Anna Janecka Tomasz Janecki Source Type: research

Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease
Eur J Med Chem. 2021 Apr 3;219:113426. doi: 10.1016/j.ejmech.2021.113426. Online ahead of print.ABSTRACTThe complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole frag...
Source: European Journal of Medicinal Chemistry - April 13, 2021 Category: Chemistry Authors: Li-Cheng Zhou Ying-Fan Liang Yi Huang Gui-Xiang Yang Lu-Lu Zheng Jia-Min Sun Yang Li Fu-Li Zhu He-Wen Qian Rui Wang Lei Ma Source Type: research

Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease
Eur J Med Chem. 2021 Apr 3;219:113426. doi: 10.1016/j.ejmech.2021.113426. Online ahead of print.ABSTRACTThe complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole frag...
Source: European Journal of Medicinal Chemistry - April 13, 2021 Category: Chemistry Authors: Li-Cheng Zhou Ying-Fan Liang Yi Huang Gui-Xiang Yang Lu-Lu Zheng Jia-Min Sun Yang Li Fu-Li Zhu He-Wen Qian Rui Wang Lei Ma Source Type: research

Discovery of chalcone analogues as novel NLRP3 inflammasome inhibitors with potent anti-inflammation activities
This study encourages further development of more potent inhibitors based on this chemical scaffold and provides a chemical tool to identify its cellular binding target.PMID:33845232 | DOI:10.1016/j.ejmech.2021.113417 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - April 12, 2021 Category: Chemistry Authors: Cheng Zhang Hu Yue Ping Sun Lei Hua Shuli Liang Yitao Ou Dan Wu Xinyi Wu Hao Chen Ying Hao Wenhui Hu Zhongjin Yang Source Type: research

Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors
In this study, the acridine ring was modified using various phenothiazine derivatives. Several resulting compounds exhibited potent enzyme-inhibiting activity towards class II HDACs when compared to the clinically approved HDAC inhibitor SAHA. Compound 4f demonstrated the highest class II HDAC inhibition (IC50 = 4.6-600 nM), as well as promotion of neurite outgrowth. Importantly, compound 4f displayed no cytotoxicity against neuron cells. Compound 4f was further evaluated for cellular effects. Altogether, these findings show a potential strategy in HDAC inhibition for treatment of the neurological disease.PMID:33845233 | D...
Source: European Journal of Medicinal Chemistry - April 12, 2021 Category: Chemistry Authors: Kai-Cheng Hsu Jung-Chun Chu Hui-Ju Tseng Chia-I Liu Hao-Ching Wang Tony Eight Lin Hong-Sheng Lee Ling-Wei Hsin Andrew H-J Wang Chien-Huang Lin Wei-Jan Huang Source Type: research

4-4-(Anilinomethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-ylbenzoic acid derivatives as potent anti-gram-positive bacterial agents
Eur J Med Chem. 2021 Apr 4;219:113402. doi: 10.1016/j.ejmech.2021.113402. Online ahead of print.ABSTRACTA collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for antibacterial activity. The majority of trifluoromethyl phenyl derivatives are highly potent growth inhibitors of Gram-positive bacteria and showed low toxicity to human cultured cells. In particular, two compounds (59 and 74) were selected for additional studies. These compounds are highly effective against Staphylococcus aureus as shown by a low minimum inhibito...
Source: European Journal of Medicinal Chemistry - April 12, 2021 Category: Chemistry Authors: Raj Kc Hansa M M K Khan M M Frangie D F Gilmore R S Shelton A V Savenka A G Basnakian S L Shuttleworth M S Smeltzer M A Alam Source Type: research

Further lead optimization on Bax activators: Design, synthesis and pharmacological evaluation of 2-fluoro-fluorene derivatives for the treatment of breast cancer
Eur J Med Chem. 2021 Apr 3;219:113427. doi: 10.1016/j.ejmech.2021.113427. Online ahead of print.ABSTRACTTo further pursue potent Bax activators with better safety profiles for the treatment of breast cancer, structural optimization was conducted based on lead compound CYD-4-61 through several strategies, including scaffold hopping on the 2-nitro-fluorene ring, replacement of the nitro group with bioisosteres to avoid potential toxicity, and further optimization on the upper pyridine by exploring diverse alkylamine linkers as a tail or replacing the pyridine with bioisosteric heterocycles. F-containing compound 22d (GL0388)...
Source: European Journal of Medicinal Chemistry - April 12, 2021 Category: Chemistry Authors: Gang Liu Hyejin Kim Pingyuan Wang Doerte R Fricke Haiying Chen Tianzhi Wang Qiang Shen Jia Zhou Source Type: research

Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor
We report herein the structure-guided development of the first potent and covalent inhibitor of ZAP-70 kinase domain. In particular, compound 18 (RDN009) showed good selectivity for ZAP-70 over structurally related Syk, and displayed potent inhibitory effects on T cell proliferation, activation, and inflammatory cytokine production. A mass spectrometry analysis further confirmed the covalent linkage between the inhibitor and ZAP-70 protein at C346. Overall, the covalent inhibitor RDN009 represents a potent and selective probe of ZAP-70 for further development for treatment of autoimmune diseases.PMID:33845236 | DOI:10.1016...
Source: European Journal of Medicinal Chemistry - April 12, 2021 Category: Chemistry Authors: Danni Rao Heng Li Xuelian Ren Yaoliang Sun Cuiyun Wen Mingyue Zheng He Huang Wei Tang Shilin Xu Source Type: research

Flavonoid-triazolyl hybrids as potential anti-hepatitis C virus agents: Synthesis and biological evaluation
Eur J Med Chem. 2021 Mar 31;218:113395. doi: 10.1016/j.ejmech.2021.113395. Online ahead of print.ABSTRACTA series of flavonoid-triazolyl hybrids were synthesized and evaluated as novel inhibitors of hepatitis C virus (HCV). The results of anti-HCV activity assays showed that most of the synthesized derivatives at a concentration of 100 μg/mL inhibited the generation of progeny virus. Among these derivatives, 10m and 10r exhibited the most potent anti-HCV activity and inhibited the production of HCV in a dose-dependent manner. Interestingly, 10m and 10r had no significant inhibitory effect on viral translation or replica...
Source: European Journal of Medicinal Chemistry - April 10, 2021 Category: Chemistry Authors: Han Zhang Xin Zheng Jichong Li Qingbo Liu Xiao-Xiao Huang Huaiwei Ding Ryosuke Suzuki Masamichi Muramatsu Shao-Jiang Song Source Type: research

Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters
Eur J Med Chem. 2021 Mar 31;218:113397. doi: 10.1016/j.ejmech.2021.113397. Online ahead of print.ABSTRACTLooking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) ...
Source: European Journal of Medicinal Chemistry - April 10, 2021 Category: Chemistry Authors: Anna Pasieka Dawid Panek Jakub Jo ńczyk Justyna Gody ń Natalia Sza łaj Gniewomir Latacz Julia Tabor Eva Mezeiova Fabien Chantegreil Jos é Dias Damijan Knez Junfeng Lu Rongbiao Pi Jan Korabecny Xavier Brazzolotto Stanislav Gobec Georg H öfner Klaus Wa Source Type: research

Flavonoid-triazolyl hybrids as potential anti-hepatitis C virus agents: Synthesis and biological evaluation
Eur J Med Chem. 2021 Mar 31;218:113395. doi: 10.1016/j.ejmech.2021.113395. Online ahead of print.ABSTRACTA series of flavonoid-triazolyl hybrids were synthesized and evaluated as novel inhibitors of hepatitis C virus (HCV). The results of anti-HCV activity assays showed that most of the synthesized derivatives at a concentration of 100 μg/mL inhibited the generation of progeny virus. Among these derivatives, 10m and 10r exhibited the most potent anti-HCV activity and inhibited the production of HCV in a dose-dependent manner. Interestingly, 10m and 10r had no significant inhibitory effect on viral translation or replica...
Source: European Journal of Medicinal Chemistry - April 10, 2021 Category: Chemistry Authors: Han Zhang Xin Zheng Jichong Li Qingbo Liu Xiao-Xiao Huang Huaiwei Ding Ryosuke Suzuki Masamichi Muramatsu Shao-Jiang Song Source Type: research

Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters
Eur J Med Chem. 2021 Mar 31;218:113397. doi: 10.1016/j.ejmech.2021.113397. Online ahead of print.ABSTRACTLooking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) ...
Source: European Journal of Medicinal Chemistry - April 10, 2021 Category: Chemistry Authors: Anna Pasieka Dawid Panek Jakub Jo ńczyk Justyna Gody ń Natalia Sza łaj Gniewomir Latacz Julia Tabor Eva Mezeiova Fabien Chantegreil Jos é Dias Damijan Knez Junfeng Lu Rongbiao Pi Jan Korabecny Xavier Brazzolotto Stanislav Gobec Georg H öfner Klaus Wa Source Type: research

Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity
Eur J Med Chem. 2021 Mar 31;218:113392. doi: 10.1016/j.ejmech.2021.113392. Online ahead of print.ABSTRACTHistone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a s...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Xin-Hui Zhang Hui-Qin Kang Yuan-Yuan Tao Yi-Han Li Jun-Ru Zhao None Ya-Gao Li-Ying Ma Hong-Min Liu Source Type: research

Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatments of Alzheimer's disease: A comprehensive review
Eur J Med Chem. 2021 Mar 27;218:113401. doi: 10.1016/j.ejmech.2021.113401. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is the most common progressive neurodegenerative disorder characterized by neuronal loss and cognitive impairment that harshly affect the elderly individuals. Currently, the available anti-AD pharmacological approaches are purely symptomatic to alleviate AD symptoms, and the curative effects of novel anti-AD drugs focused on Aβ target are disappointing. Hence, there is a tremendous need to adjust AD therapeutic targets and discover novel anti-AD agents. In AD, mitochondrial dysfunction grad...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Xin Jin Jia-Ling Guo Lin Wang Xin Zhong Wei-Fan Yao Hua Gao Ming-Yan Liu Source Type: research

Novel potent bifunctional carboxylesterase inhibitors based on a polyfluoroalkyl-2-imino-1,3-dione scaffold
Eur J Med Chem. 2021 Mar 15;218:113385. doi: 10.1016/j.ejmech.2021.113385. Online ahead of print.ABSTRACTAn expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc)2-catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase (CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, b...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Galina F Makhaeva Sofya V Lushchekina Natalia P Boltneva Olga G Serebryakova Nadezhda V Kovaleva Elena V Rudakova Natalia A Elkina Evgeny V Shchegolkov Yanina V Burgart Tatyana S Stupina Alexey A Terentiev Eugene V Radchenko Vladimir A Palyulin Victor I S Source Type: research

Discovery of novel potent migrastatic Thiazolo[5,4-b]pyridines targeting Lysyl-tRNA synthetase (KRS) for treatment of Cancer metastasis
Eur J Med Chem. 2021 Mar 30;218:113405. doi: 10.1016/j.ejmech.2021.113405. Online ahead of print.ABSTRACTRecently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studi...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Seungbeom Lee Nam Hoon Kwon Bokyung Seo Jin Young Lee Hye Young Cho Kyeojin Kim Hyun Su Kim Kiwon Jung Young Ho Jeon Sunghoon Kim Young-Ger Suh Source Type: research

Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity
Eur J Med Chem. 2021 Mar 31;218:113392. doi: 10.1016/j.ejmech.2021.113392. Online ahead of print.ABSTRACTHistone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a s...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Xin-Hui Zhang Hui-Qin Kang Yuan-Yuan Tao Yi-Han Li Jun-Ru Zhao None Ya-Gao Li-Ying Ma Hong-Min Liu Source Type: research

Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatments of Alzheimer's disease: A comprehensive review
Eur J Med Chem. 2021 Mar 27;218:113401. doi: 10.1016/j.ejmech.2021.113401. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is the most common progressive neurodegenerative disorder characterized by neuronal loss and cognitive impairment that harshly affect the elderly individuals. Currently, the available anti-AD pharmacological approaches are purely symptomatic to alleviate AD symptoms, and the curative effects of novel anti-AD drugs focused on Aβ target are disappointing. Hence, there is a tremendous need to adjust AD therapeutic targets and discover novel anti-AD agents. In AD, mitochondrial dysfunction grad...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Xin Jin Jia-Ling Guo Lin Wang Xin Zhong Wei-Fan Yao Hua Gao Ming-Yan Liu Source Type: research

Novel potent bifunctional carboxylesterase inhibitors based on a polyfluoroalkyl-2-imino-1,3-dione scaffold
Eur J Med Chem. 2021 Mar 15;218:113385. doi: 10.1016/j.ejmech.2021.113385. Online ahead of print.ABSTRACTAn expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc)2-catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase (CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, b...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Galina F Makhaeva Sofya V Lushchekina Natalia P Boltneva Olga G Serebryakova Nadezhda V Kovaleva Elena V Rudakova Natalia A Elkina Evgeny V Shchegolkov Yanina V Burgart Tatyana S Stupina Alexey A Terentiev Eugene V Radchenko Vladimir A Palyulin Victor I S Source Type: research

Discovery of novel potent migrastatic Thiazolo[5,4-b]pyridines targeting Lysyl-tRNA synthetase (KRS) for treatment of Cancer metastasis
Eur J Med Chem. 2021 Mar 30;218:113405. doi: 10.1016/j.ejmech.2021.113405. Online ahead of print.ABSTRACTRecently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studi...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Seungbeom Lee Nam Hoon Kwon Bokyung Seo Jin Young Lee Hye Young Cho Kyeojin Kim Hyun Su Kim Kiwon Jung Young Ho Jeon Sunghoon Kim Young-Ger Suh Source Type: research

Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity
Eur J Med Chem. 2021 Mar 31;218:113392. doi: 10.1016/j.ejmech.2021.113392. Online ahead of print.ABSTRACTHistone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a s...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Xin-Hui Zhang Hui-Qin Kang Yuan-Yuan Tao Yi-Han Li Jun-Ru Zhao None Ya-Gao Li-Ying Ma Hong-Min Liu Source Type: research

Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatments of Alzheimer's disease: A comprehensive review
Eur J Med Chem. 2021 Mar 27;218:113401. doi: 10.1016/j.ejmech.2021.113401. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is the most common progressive neurodegenerative disorder characterized by neuronal loss and cognitive impairment that harshly affect the elderly individuals. Currently, the available anti-AD pharmacological approaches are purely symptomatic to alleviate AD symptoms, and the curative effects of novel anti-AD drugs focused on Aβ target are disappointing. Hence, there is a tremendous need to adjust AD therapeutic targets and discover novel anti-AD agents. In AD, mitochondrial dysfunction grad...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Xin Jin Jia-Ling Guo Lin Wang Xin Zhong Wei-Fan Yao Hua Gao Ming-Yan Liu Source Type: research

Novel potent bifunctional carboxylesterase inhibitors based on a polyfluoroalkyl-2-imino-1,3-dione scaffold
Eur J Med Chem. 2021 Mar 15;218:113385. doi: 10.1016/j.ejmech.2021.113385. Online ahead of print.ABSTRACTAn expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc)2-catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase (CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, b...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Galina F Makhaeva Sofya V Lushchekina Natalia P Boltneva Olga G Serebryakova Nadezhda V Kovaleva Elena V Rudakova Natalia A Elkina Evgeny V Shchegolkov Yanina V Burgart Tatyana S Stupina Alexey A Terentiev Eugene V Radchenko Vladimir A Palyulin Victor I S Source Type: research

Discovery of novel potent migrastatic Thiazolo[5,4-b]pyridines targeting Lysyl-tRNA synthetase (KRS) for treatment of Cancer metastasis
Eur J Med Chem. 2021 Mar 30;218:113405. doi: 10.1016/j.ejmech.2021.113405. Online ahead of print.ABSTRACTRecently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studi...
Source: European Journal of Medicinal Chemistry - April 8, 2021 Category: Chemistry Authors: Seungbeom Lee Nam Hoon Kwon Bokyung Seo Jin Young Lee Hye Young Cho Kyeojin Kim Hyun Su Kim Kiwon Jung Young Ho Jeon Sunghoon Kim Young-Ger Suh Source Type: research

Square planar Au(III), Pt(II) and Cu(II) complexes with quinoline-substituted 2,2':6',2 ″-terpyridine ligands: From in vitro to in vivo biological properties
Eur J Med Chem. 2021 Mar 26;218:113404. doi: 10.1016/j.ejmech.2021.113404. Online ahead of print.ABSTRACTCancer is the second leading cause of death worldwide. Cisplatin has challenged cancer treatment; however, resistance and side effects hamper its use. New agents displaying improved activity and more reduced side effects relative to cisplatin are needed. In this work we present the synthesis, characterization and biological activities of three complexes with quinoline-substituted 2,2':6',2″-terpyridine ligand: [Pt(4'-(2-quin)-terpy)Cl](SO3CF3) (1), [Au(4'-(2-quin)-terpy)Cl](PF6)2·CH3CN (2) and [Cu(4'-(2-qui...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Katarzyna Choroba Barbara Machura Agata Szlapa-Kula Jan G Malecki Luis Raposo Catarina Roma-Rodrigues Sandra Cordeiro Pedro V Baptista Alexandra R Fernandes Source Type: research

Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation
Eur J Med Chem. 2021 Mar 26;218:113391. doi: 10.1016/j.ejmech.2021.113391. Online ahead of print.ABSTRACTCDK8 is deregulated in multiple types of human cancer and is viewed as a therapeutic target for the treatment of the disease. Accordingly, the search for small-molecule inhibitors of CDK8 is being intensified. Capitalising on our initial discovery of AU1-100, a potent CDK8 inhibitor yet with a limited degree of kinase selectivity, a structure-based optimisation was carried out, with a series of new multi-substituted pyridines rationally designed, chemically prepared and biologically evaluated. Such endeavour has culmina...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Mingfeng Yu Yi Long Yuchao Yang Manjun Li Theodosia Teo Benjamin Noll Stephen Philip Shudong Wang Source Type: research

Design, synthesis and biological activity of N-(amino)piperazine-containing benzothiazinones against Mycobacterium tuberculosis
Eur J Med Chem. 2021 Mar 28;218:113398. doi: 10.1016/j.ejmech.2021.113398. Online ahead of print.ABSTRACTA series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent in vitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: 64 μg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compoun...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Apeng Wang Shijie Xu Yun Chai Guimin Xia Bin Wang Kai Lv Chao Ma Dan Wang Aoyu Wang Xiaoyu Qin Mingliang Liu Yu Lu Source Type: research

Structure property relationships of N-acylsulfonamides and related bioisosteres
Eur J Med Chem. 2021 Mar 28;218:113399. doi: 10.1016/j.ejmech.2021.113399. Online ahead of print.ABSTRACTThe N-acylsulfonamide functional group is a feature of the pharmacophore of several biologically active molecules, including marketed drugs. Although this acidic moiety presents multiple points of attachments that could be exploited to introduce structural diversification, depending on the circumstances, the replacement of the functional group itself with a suitable surrogate, or bioisostere, may be desirable. A number of N-acylsulfonamide bioisosteres have been developed over the years that provide opportunities to mod...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Karol R Francisco Carmine Varricchio Thomas J Paniak Marisa C Kozlowski Andrea Brancale Carlo Ballatore Source Type: research

An insight in anti-malarial potential of indole scaffold: A review
Eur J Med Chem. 2021 Mar 27;218:113400. doi: 10.1016/j.ejmech.2021.113400. Online ahead of print.ABSTRACTMalaria is a major parasitic disease in tropical and sub-tropical regions. Pertaining to the sustaining resistance in malarial parasite against the available drugs, novel treatment options are the need of the hour. In this resolve recently, focus has shifted to finding the natural alternatives that possess anti-plasmodial activity for combatting malaria. Drawing on the text written in ancient scriptures and Ayurveda, natural compounds are now being screened for their therapeutic properties. Indole is one such natural co...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Mehak Chauhan Anjali Saxena Biswajit Saha Source Type: research

A comprehensive review of chemistry and pharmacological aspects of natural cyanobacterial azoline-based circular and linear oligopeptides
Eur J Med Chem. 2021 Mar 26;218:113406. doi: 10.1016/j.ejmech.2021.113406. Online ahead of print.ABSTRACTThe cyanobacterial oligopeptides are recognized for being highly selective, efficacious and relatively safer compounds with diverse bioactivities. Azoline-based natural compounds consist of heterocycles which are reduced analogues of five-membered heterocyclic azoles. Among other varieties of azoline-based natural compounds, the heteropeptides bearing oxazoline or thiazoline heterocycles possess intrinsic structural properties with captivating pharmacological profiles, representing excellent templates for the design of ...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Sunita Dahiya Rajiv Dahiya Source Type: research

Discovery of new pyrimidopyrrolizine/indolizine-based derivatives as P-glycoprotein inhibitors: Design, synthesis, cytotoxicity, and MDR reversal activities
Eur J Med Chem. 2021 Mar 27;218:113403. doi: 10.1016/j.ejmech.2021.113403. Online ahead of print.ABSTRACTTargeting P-glycoprotein (P-gp, ABCB1 transporter), which plays an essential role in multi-drug resistance (MDR) in cancers, with new cytotoxic agents is a promising strategy in cancer chemotherapy. In the current study, we report the synthesis of thirteen novel pyrimidopyrrolizine, pyrimidoindolizine, and diazepinopyrrolizine derivatives. The new compounds exhibited cytotoxic activities against MCF7, A2780 and HT29 cancer cell lines (IC50 = 0.02-19.58 μM) and MRC5 (IC50 = 0.17-20.57 μM). The six most active compo...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Ahmed M Shawky Ashraf N Abdalla Nashwa A Ibrahim Mohammed A S Abourehab Ahmed M Gouda Source Type: research

Square planar Au(III), Pt(II) and Cu(II) complexes with quinoline-substituted 2,2':6',2 ″-terpyridine ligands: From in vitro to in vivo biological properties
Eur J Med Chem. 2021 Mar 26;218:113404. doi: 10.1016/j.ejmech.2021.113404. Online ahead of print.ABSTRACTCancer is the second leading cause of death worldwide. Cisplatin has challenged cancer treatment; however, resistance and side effects hamper its use. New agents displaying improved activity and more reduced side effects relative to cisplatin are needed. In this work we present the synthesis, characterization and biological activities of three complexes with quinoline-substituted 2,2':6',2″-terpyridine ligand: [Pt(4'-(2-quin)-terpy)Cl](SO3CF3) (1), [Au(4'-(2-quin)-terpy)Cl](PF6)2·CH3CN (2) and [Cu(4'-(2-qui...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Katarzyna Choroba Barbara Machura Agata Szlapa-Kula Jan G Malecki Luis Raposo Catarina Roma-Rodrigues Sandra Cordeiro Pedro V Baptista Alexandra R Fernandes Source Type: research

Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation
Eur J Med Chem. 2021 Mar 26;218:113391. doi: 10.1016/j.ejmech.2021.113391. Online ahead of print.ABSTRACTCDK8 is deregulated in multiple types of human cancer and is viewed as a therapeutic target for the treatment of the disease. Accordingly, the search for small-molecule inhibitors of CDK8 is being intensified. Capitalising on our initial discovery of AU1-100, a potent CDK8 inhibitor yet with a limited degree of kinase selectivity, a structure-based optimisation was carried out, with a series of new multi-substituted pyridines rationally designed, chemically prepared and biologically evaluated. Such endeavour has culmina...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Mingfeng Yu Yi Long Yuchao Yang Manjun Li Theodosia Teo Benjamin Noll Stephen Philip Shudong Wang Source Type: research

Design, synthesis and biological activity of N-(amino)piperazine-containing benzothiazinones against Mycobacterium tuberculosis
Eur J Med Chem. 2021 Mar 28;218:113398. doi: 10.1016/j.ejmech.2021.113398. Online ahead of print.ABSTRACTA series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent in vitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: 64 μg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compoun...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Apeng Wang Shijie Xu Yun Chai Guimin Xia Bin Wang Kai Lv Chao Ma Dan Wang Aoyu Wang Xiaoyu Qin Mingliang Liu Yu Lu Source Type: research

Structure property relationships of N-acylsulfonamides and related bioisosteres
Eur J Med Chem. 2021 Mar 28;218:113399. doi: 10.1016/j.ejmech.2021.113399. Online ahead of print.ABSTRACTThe N-acylsulfonamide functional group is a feature of the pharmacophore of several biologically active molecules, including marketed drugs. Although this acidic moiety presents multiple points of attachments that could be exploited to introduce structural diversification, depending on the circumstances, the replacement of the functional group itself with a suitable surrogate, or bioisostere, may be desirable. A number of N-acylsulfonamide bioisosteres have been developed over the years that provide opportunities to mod...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Karol R Francisco Carmine Varricchio Thomas J Paniak Marisa C Kozlowski Andrea Brancale Carlo Ballatore Source Type: research

An insight in anti-malarial potential of indole scaffold: A review
Eur J Med Chem. 2021 Mar 27;218:113400. doi: 10.1016/j.ejmech.2021.113400. Online ahead of print.ABSTRACTMalaria is a major parasitic disease in tropical and sub-tropical regions. Pertaining to the sustaining resistance in malarial parasite against the available drugs, novel treatment options are the need of the hour. In this resolve recently, focus has shifted to finding the natural alternatives that possess anti-plasmodial activity for combatting malaria. Drawing on the text written in ancient scriptures and Ayurveda, natural compounds are now being screened for their therapeutic properties. Indole is one such natural co...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Mehak Chauhan Anjali Saxena Biswajit Saha Source Type: research

A comprehensive review of chemistry and pharmacological aspects of natural cyanobacterial azoline-based circular and linear oligopeptides
Eur J Med Chem. 2021 Mar 26;218:113406. doi: 10.1016/j.ejmech.2021.113406. Online ahead of print.ABSTRACTThe cyanobacterial oligopeptides are recognized for being highly selective, efficacious and relatively safer compounds with diverse bioactivities. Azoline-based natural compounds consist of heterocycles which are reduced analogues of five-membered heterocyclic azoles. Among other varieties of azoline-based natural compounds, the heteropeptides bearing oxazoline or thiazoline heterocycles possess intrinsic structural properties with captivating pharmacological profiles, representing excellent templates for the design of ...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Sunita Dahiya Rajiv Dahiya Source Type: research

Discovery of new pyrimidopyrrolizine/indolizine-based derivatives as P-glycoprotein inhibitors: Design, synthesis, cytotoxicity, and MDR reversal activities
Eur J Med Chem. 2021 Mar 27;218:113403. doi: 10.1016/j.ejmech.2021.113403. Online ahead of print.ABSTRACTTargeting P-glycoprotein (P-gp, ABCB1 transporter), which plays an essential role in multi-drug resistance (MDR) in cancers, with new cytotoxic agents is a promising strategy in cancer chemotherapy. In the current study, we report the synthesis of thirteen novel pyrimidopyrrolizine, pyrimidoindolizine, and diazepinopyrrolizine derivatives. The new compounds exhibited cytotoxic activities against MCF7, A2780 and HT29 cancer cell lines (IC50 = 0.02-19.58 μM) and MRC5 (IC50 = 0.17-20.57 μM). The six most active compo...
Source: European Journal of Medicinal Chemistry - April 6, 2021 Category: Chemistry Authors: Ahmed M Shawky Ashraf N Abdalla Nashwa A Ibrahim Mohammed A S Abourehab Ahmed M Gouda Source Type: research

Bioinspired imidazo[1,2-a:4,5-c']dipyridines with dual antiproliferative and anti-migrative properties in human cancer cells: The SAR investigation
Eur J Med Chem. 2021 Feb 13;218:113258. doi: 10.1016/j.ejmech.2021.113258. Online ahead of print.ABSTRACTHerein, we report the design, synthesis and evaluation of novel bioinspired imidazo[1,2-a:4,5c']dipyridines. The structural optimization identified four anti-proliferative compounds. Compounds 11, 18, 19 and 20 exhibited excellent anticancer activities in vitro with IC50 of 0.4-5 μM against three human cancer cell lines (MDA-MB-468, MDA-MB-435s and MDA-MB-231). These four compounds induced apoptosis in MDA-MB-231 cells in a dose-dependent manner, targeting different apoptotic proteins expression: 11 increased the exp...
Source: European Journal of Medicinal Chemistry - April 4, 2021 Category: Chemistry Authors: Abdulrahim A Alzain Lucie Brisson Pierre-Olivier Delaye M élanie Pénichon St éphanie Chadet Pierre Besson St éphan Chevalier Hassan Allouchi Magdi A Mohamed S ébastien Roger C écile Enguehard-Gueiffier Source Type: research

Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2
Eur J Med Chem. 2021 Mar 26;218:113394. doi: 10.1016/j.ejmech.2021.113394. Online ahead of print.ABSTRACTHerein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold,>30-fold and>30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed...
Source: European Journal of Medicinal Chemistry - April 4, 2021 Category: Chemistry Authors: Pengfei Xu Pei Shen Hai Wang Lian Qin Jie Ren Qiushuang Sun Raoling Ge Jinlei Bian Yi Zhong Zhiyu Li JuBo Wang Zhixia Qiu Source Type: research

Bioinspired imidazo[1,2-a:4,5-c']dipyridines with dual antiproliferative and anti-migrative properties in human cancer cells: The SAR investigation
Eur J Med Chem. 2021 Feb 13;218:113258. doi: 10.1016/j.ejmech.2021.113258. Online ahead of print.ABSTRACTHerein, we report the design, synthesis and evaluation of novel bioinspired imidazo[1,2-a:4,5c']dipyridines. The structural optimization identified four anti-proliferative compounds. Compounds 11, 18, 19 and 20 exhibited excellent anticancer activities in vitro with IC50 of 0.4-5 μM against three human cancer cell lines (MDA-MB-468, MDA-MB-435s and MDA-MB-231). These four compounds induced apoptosis in MDA-MB-231 cells in a dose-dependent manner, targeting different apoptotic proteins expression: 11 increased the exp...
Source: European Journal of Medicinal Chemistry - April 4, 2021 Category: Chemistry Authors: Abdulrahim A Alzain Lucie Brisson Pierre-Olivier Delaye M élanie Pénichon St éphanie Chadet Pierre Besson St éphan Chevalier Hassan Allouchi Magdi A Mohamed S ébastien Roger C écile Enguehard-Gueiffier Source Type: research

Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2
Eur J Med Chem. 2021 Mar 26;218:113394. doi: 10.1016/j.ejmech.2021.113394. Online ahead of print.ABSTRACTHerein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold,>30-fold and>30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed...
Source: European Journal of Medicinal Chemistry - April 4, 2021 Category: Chemistry Authors: Pengfei Xu Pei Shen Hai Wang Lian Qin Jie Ren Qiushuang Sun Raoling Ge Jinlei Bian Yi Zhong Zhiyu Li JuBo Wang Zhixia Qiu Source Type: research

Bioinspired imidazo[1,2-a:4,5-c']dipyridines with dual antiproliferative and anti-migrative properties in human cancer cells: The SAR investigation
Eur J Med Chem. 2021 Feb 13;218:113258. doi: 10.1016/j.ejmech.2021.113258. Online ahead of print.ABSTRACTHerein, we report the design, synthesis and evaluation of novel bioinspired imidazo[1,2-a:4,5c']dipyridines. The structural optimization identified four anti-proliferative compounds. Compounds 11, 18, 19 and 20 exhibited excellent anticancer activities in vitro with IC50 of 0.4-5 μM against three human cancer cell lines (MDA-MB-468, MDA-MB-435s and MDA-MB-231). These four compounds induced apoptosis in MDA-MB-231 cells in a dose-dependent manner, targeting different apoptotic proteins expression: 11 increased the exp...
Source: European Journal of Medicinal Chemistry - April 4, 2021 Category: Chemistry Authors: Abdulrahim A Alzain Lucie Brisson Pierre-Olivier Delaye M élanie Pénichon St éphanie Chadet Pierre Besson St éphan Chevalier Hassan Allouchi Magdi A Mohamed S ébastien Roger C écile Enguehard-Gueiffier Source Type: research

Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2
Eur J Med Chem. 2021 Mar 26;218:113394. doi: 10.1016/j.ejmech.2021.113394. Online ahead of print.ABSTRACTHerein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold,>30-fold and>30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed...
Source: European Journal of Medicinal Chemistry - April 4, 2021 Category: Chemistry Authors: Pengfei Xu Pei Shen Hai Wang Lian Qin Jie Ren Qiushuang Sun Raoling Ge Jinlei Bian Yi Zhong Zhiyu Li JuBo Wang Zhixia Qiu Source Type: research

Structure-based drug design of an inhibitor of the SARS-CoV-2 (COVID-19) main protease using free software: A tutorial for students and scientists
Eur J Med Chem. 2021 Mar 20;218:113390. doi: 10.1016/j.ejmech.2021.113390. Online ahead of print.ABSTRACTThis paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (Mpro) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then us...
Source: European Journal of Medicinal Chemistry - April 3, 2021 Category: Chemistry Authors: Sheng Zhang Maj Krumberger Michael A Morris Chelsea Marie T Parrocha Adam G Kreutzer James S Nowick Source Type: research

Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction
Eur J Med Chem. 2021 Mar 17;218:113383. doi: 10.1016/j.ejmech.2021.113383. Online ahead of print.ABSTRACTHistone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-ben...
Source: European Journal of Medicinal Chemistry - April 2, 2021 Category: Chemistry Authors: Zheng Guo Zixue Zhang Yi Zhang Guan Wang Ziyi Huang Qinwei Zhang Jianqi Li Source Type: research

New organoselenides (NSAIDs-Se derivatives) as potential anticancer agents: Synthesis, biological evaluation and in silico calculations
Eur J Med Chem. 2021 Mar 20;218:113384. doi: 10.1016/j.ejmech.2021.113384. Online ahead of print.ABSTRACTHerein we reported the synthesis of twenty new organoselenium compounds (2a-2j and 3a-3j) based on the hybridization of nonsteroidal antiinflammatory drugs (NSAIDs) skeleton and organoselenium motif (-SeCN and -SeCF3), the anticancer activity was evaluated against four types of cancer cell lines, Caco-2 (human colon adenocarcinoma cells), BGC-823 (human gastric cancer cells), MCF-7 (human breast adenocarcinoma cells), PC-3 (human prostatic cancer cells). Interestingly, the introduction of the -SeCN or -SeCF3 moiety in c...
Source: European Journal of Medicinal Chemistry - April 2, 2021 Category: Chemistry Authors: Xianran He Yousong Nie Min Zhong Shaolei Li Xiaolong Li Yi Guo Zhenming Liu Yangguang Gao Fei Ding Dan Wen Yongmin Zhang Source Type: research

Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction
Eur J Med Chem. 2021 Mar 17;218:113383. doi: 10.1016/j.ejmech.2021.113383. Online ahead of print.ABSTRACTHistone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-ben...
Source: European Journal of Medicinal Chemistry - April 2, 2021 Category: Chemistry Authors: Zheng Guo Zixue Zhang Yi Zhang Guan Wang Ziyi Huang Qinwei Zhang Jianqi Li Source Type: research

New organoselenides (NSAIDs-Se derivatives) as potential anticancer agents: Synthesis, biological evaluation and in silico calculations
Eur J Med Chem. 2021 Mar 20;218:113384. doi: 10.1016/j.ejmech.2021.113384. Online ahead of print.ABSTRACTHerein we reported the synthesis of twenty new organoselenium compounds (2a-2j and 3a-3j) based on the hybridization of nonsteroidal antiinflammatory drugs (NSAIDs) skeleton and organoselenium motif (-SeCN and -SeCF3), the anticancer activity was evaluated against four types of cancer cell lines, Caco-2 (human colon adenocarcinoma cells), BGC-823 (human gastric cancer cells), MCF-7 (human breast adenocarcinoma cells), PC-3 (human prostatic cancer cells). Interestingly, the introduction of the -SeCN or -SeCF3 moiety in c...
Source: European Journal of Medicinal Chemistry - April 2, 2021 Category: Chemistry Authors: Xianran He Yousong Nie Min Zhong Shaolei Li Xiaolong Li Yi Guo Zhenming Liu Yangguang Gao Fei Ding Dan Wen Yongmin Zhang Source Type: research

Design and synthesis of 1H-pyrazolo[3,4-b]pyridines targeting mitogen-activated protein kinase kinase 4 (MKK4) - A promising target for liver regeneration
Eur J Med Chem. 2021 Mar 17;218:113371. doi: 10.1016/j.ejmech.2021.113371. Online ahead of print.ABSTRACTCurrently, the therapeutic options for treatment of liver failure are very limited. As mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified by in vivo RNAi experiments to be a major regulator in hepatocyte regeneration, we pursued the development of a small molecule targeting this protein kinase. Starting from the approved BRAFV600E inhibitor vemurafenib (8), that showed a high off-target affinity to MKK4 in an initial screening, we followed a scaffold-hopping approach, changing the core heteroc...
Source: European Journal of Medicinal Chemistry - April 1, 2021 Category: Chemistry Authors: Bent Pfaffenrot Philip Kl övekorn Michael Juchum Roland Selig Wolfgang Albrecht Lars Zender Stefan A Laufer Source Type: research