Pan- and isoform-specific inhibition of Hsp90: Design strategy and recent advances
Eur J Med Chem. 2022 Jun 7;238:114516. doi: 10.1016/j.ejmech.2022.114516. Online ahead of print.ABSTRACTIn the past few decades, the development of heat shock protein 90 (Hsp90) inhibitors for cancer treatment has not stopped. About twenty compounds have been evaluated in the clinical trials, but the FDA approved none of them because of toxic effects and/or not enough efficacies. Insufficient isoform selectivity has been considered as one of the reasons for these failures recently. Therefore, developing isoform-selective Hsp90 inhibitors could probably make great progress in searching for therapeutic agents for cancer as w...
Source: European Journal of Medicinal Chemistry - June 12, 2022 Category: Chemistry Authors: Jing Yu Chao Zhang Chun Song Source Type: research

Discovery of highly potent and selective CRBN-recruiting EGFR < sup > L858R/T790M < /sup > degraders in vivo
Eur J Med Chem. 2022 Jun 6;238:114509. doi: 10.1016/j.ejmech.2022.114509. Online ahead of print.ABSTRACTCurrently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development. Therefore, we designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders. Among the...
Source: European Journal of Medicinal Chemistry - June 12, 2022 Category: Chemistry Authors: Wenjuan Zhang Pengyun Li Shiyang Sun Changkai Jia Ning Yang Xiaomei Zhuang Zhibing Zheng Song Li Source Type: research

The polyamino-isoprenyl potentiator NV716 revives disused antibiotics against Gram-negative bacteria in broth, infected monocytes, or biofilms, by disturbing the barrier effect of their outer membrane
Eur J Med Chem. 2022 May 27;238:114496. doi: 10.1016/j.ejmech.2022.114496. Online ahead of print.ABSTRACTPotentiators can improve antibiotic activity against difficult-to-treat Gram-negative bacteria like Escherichia coli, Klebsiella pneumoniae or Acinetobacter baumannii. They represent an appealing strategy in view of the paucity of therapeutic alternatives in case of multidrug resistance. Here, we examine the ability of the polyamino-isoprenyl compound NV716 to restore the activity of a series of disused antibiotics (rifampicin, azithromycin, linezolid, fusidic acid, novobiocin, chloramphenicol, and doxycycline, plus cip...
Source: European Journal of Medicinal Chemistry - June 12, 2022 Category: Chemistry Authors: Gang Wang Jean-Michel Brunel Hector Rodriguez-Villalobos Jean-Michel Bolla Fran çoise Van Bambeke Source Type: research

Identification and anti-tumor evaluation of 3-acyl-indol-based 2,4-diarylaminopyrimidine analogues as potent ALK inhibitors capable of overcoming drug-resistant mutants
Eur J Med Chem. 2022 May 30;238:114493. doi: 10.1016/j.ejmech.2022.114493. Online ahead of print.ABSTRACTA series of novel 2,4-diarylaminopyrimidine analogues (G-1∼G-8 and I-1∼I-24) were rationally designed by incorporating 2-alkyl-3-acyl-1H-indol fragment to interact with the hydrophobic region of the intractable ALKG1202R mutant. Wherein, compound I-24 bearing a 2-methyl-3-dimethylformamido-1H-indol moiety was identified as the most promising ALK inhibitor with IC50 values below 4 nM against ALKWT, ALKL1196M and ALKG1202R, accompanied by concrete down-regulation of phospho-ALK and its relative downstream signaling. S...
Source: European Journal of Medicinal Chemistry - June 12, 2022 Category: Chemistry Authors: Ming Guo Hao Wang Jing Yang Xinyu Wang Jiahao Zhang Shuyu Liu Shangfei Wei Nan Jiang Xin Zhai Source Type: research

Design and synthesis of water-soluble prodrugs of rifabutin for intraveneous administration
Eur J Med Chem. 2022 Jun 6;238:114515. doi: 10.1016/j.ejmech.2022.114515. Online ahead of print.ABSTRACTAcinetobacter baumannii is a gram-negative bacterium causing severe hospital-acquired infections such as bloodstream infections or pneumonia. Moreover, multidrug resistant A. baumannii becomes prevalent in many hospitals. Consequently, the World Health Organization made this bacterium a critical priority for the research and development of new antibiotics. Rifabutin, a semisynthetic product from the rifamycin class, was recently found to be very active in nutrient-limited eukaryotic cell culture medium against various A....
Source: European Journal of Medicinal Chemistry - June 12, 2022 Category: Chemistry Authors: Kevin Antraygues Mathieu Maingot Birgit Schellhorn Vincent Trebosc Marc Gitzinger Benoit Deprez Olivier Defert Glenn E Dale Marilyne Bourotte Sergio Lociuro Nicolas Willand Source Type: research

Pan- and isoform-specific inhibition of Hsp90: Design strategy and recent advances
Eur J Med Chem. 2022 Jun 7;238:114516. doi: 10.1016/j.ejmech.2022.114516. Online ahead of print.ABSTRACTIn the past few decades, the development of heat shock protein 90 (Hsp90) inhibitors for cancer treatment has not stopped. About twenty compounds have been evaluated in the clinical trials, but the FDA approved none of them because of toxic effects and/or not enough efficacies. Insufficient isoform selectivity has been considered as one of the reasons for these failures recently. Therefore, developing isoform-selective Hsp90 inhibitors could probably make great progress in searching for therapeutic agents for cancer as w...
Source: European Journal of Medicinal Chemistry - June 12, 2022 Category: Chemistry Authors: Jing Yu Chao Zhang Chun Song Source Type: research

Discovery of highly potent and selective CRBN-recruiting EGFR < sup > L858R/T790M < /sup > degraders in vivo
Eur J Med Chem. 2022 Jun 6;238:114509. doi: 10.1016/j.ejmech.2022.114509. Online ahead of print.ABSTRACTCurrently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development. Therefore, we designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders. Among the...
Source: European Journal of Medicinal Chemistry - June 12, 2022 Category: Chemistry Authors: Wenjuan Zhang Pengyun Li Shiyang Sun Changkai Jia Ning Yang Xiaomei Zhuang Zhibing Zheng Song Li Source Type: research

Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer's disease
In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC50 = 0.28 μM) and PDE4D (IC50 = 1.88 μM). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed m...
Source: European Journal of Medicinal Chemistry - June 11, 2022 Category: Chemistry Authors: Jie Liu Lu Liu Lei Zheng Kai-Wen Feng Hai-Tao Wang Jiang-Ping Xu Zhong-Zhen Zhou Source Type: research

Design, synthesis and anti-inflammatory evaluation of aloe-emodin derivatives as potential modulators of Akt, NF- κB and JNK signaling pathways
Eur J Med Chem. 2022 Jun 2;238:114511. doi: 10.1016/j.ejmech.2022.114511. Online ahead of print.ABSTRACTTo discover novel anti-inflammatory agents, a series of nitrogen-containing derivatives of aloe-emodin were designed and synthesized. The anti-inflammatory activities of all synthesized derivatives were screened by evaluating their inhibitory effects on LPS-induced nitric oxide production in RAW264.7 macrophages. The preliminary structure-activity relationship was determined. Among them, 2i exhibited the best nitric oxide inhibitory activity (IC50 = 3.15 μM), with no obvious toxicity. Further evaluation of the inhibitor...
Source: European Journal of Medicinal Chemistry - June 11, 2022 Category: Chemistry Authors: Hai Shang Jing Guo Pengtao Wang Lingyu Li Yu Tian Xiaoxue Li Zhongmei Zou Source Type: research

Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer's disease
In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC50 = 0.28 μM) and PDE4D (IC50 = 1.88 μM). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed m...
Source: European Journal of Medicinal Chemistry - June 11, 2022 Category: Chemistry Authors: Jie Liu Lu Liu Lei Zheng Kai-Wen Feng Hai-Tao Wang Jiang-Ping Xu Zhong-Zhen Zhou Source Type: research

Design, synthesis and anti-inflammatory evaluation of aloe-emodin derivatives as potential modulators of Akt, NF- κB and JNK signaling pathways
Eur J Med Chem. 2022 Jun 2;238:114511. doi: 10.1016/j.ejmech.2022.114511. Online ahead of print.ABSTRACTTo discover novel anti-inflammatory agents, a series of nitrogen-containing derivatives of aloe-emodin were designed and synthesized. The anti-inflammatory activities of all synthesized derivatives were screened by evaluating their inhibitory effects on LPS-induced nitric oxide production in RAW264.7 macrophages. The preliminary structure-activity relationship was determined. Among them, 2i exhibited the best nitric oxide inhibitory activity (IC50 = 3.15 μM), with no obvious toxicity. Further evaluation of the inhibitor...
Source: European Journal of Medicinal Chemistry - June 11, 2022 Category: Chemistry Authors: Hai Shang Jing Guo Pengtao Wang Lingyu Li Yu Tian Xiaoxue Li Zhongmei Zou Source Type: research

Contemporary mTOR inhibitor scaffolds to diseases breakdown: A patent review (2015-2021)
Eur J Med Chem. 2022 May 28;238:114498. doi: 10.1016/j.ejmech.2022.114498. Online ahead of print.ABSTRACTMechanistic target of rapamycin (mTOR) is a highly conserved protein kinase acting as a central regulator of cell functions. The kinase forms two distinct mTOR complexes termed as mTORC1 and mTORC2. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR represent a rational approach in the treatment of numerous human diseases. Rapamycin is a potent natural inhibitor of mTOR exhibiting significant antitumor and immunosuppressive activity. Derivatization of rapa...
Source: European Journal of Medicinal Chemistry - June 10, 2022 Category: Chemistry Authors: Patrik Oleksak Eugenie Nepovimova Zofia Chrienova Kamil Musilek Jiri Patocka Kamil Kuca Source Type: research

Discovery of 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 main protease
Eur J Med Chem. 2022 Jun 3;238:114508. doi: 10.1016/j.ejmech.2022.114508. Online ahead of print.ABSTRACTThe COVID-19 posed a serious threat to human life and health, and SARS-CoV-2 Mpro has been considered as an attractive drug target for the treatment of COVID-19. Herein, we report 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 Mpro developed by in-house library screening and biological evaluation. Similarity search led to the identification of compound F8-S43 with the enzymatic IC50 value of 10.76 μM. Further structure-based drug design and synthetic optimization uncovere...
Source: European Journal of Medicinal Chemistry - June 10, 2022 Category: Chemistry Authors: Xiaodong Dou Qi Sun Guofeng Xu Yameng Liu Caifang Zhang Bingding Wang Yangbin Lu Zheng Guo Lingyu Su Tongyu Huo Xinyi Zhao Chen Wang Zhongtian Yu Song Song Liangren Zhang Zhenming Liu Luhua Lai Ning Jiao Source Type: research

Novel design of multifunctional nanozymes based on tumor microenvironment for diagnosis and therapy
Eur J Med Chem. 2022 May 13;238:114456. doi: 10.1016/j.ejmech.2022.114456. Online ahead of print.ABSTRACTNanozymes have entranced considerable concern since they provide a likelihood strategy for performing the integration of diagnosis and therapy. Nanozymes, as emerging nanomaterials with enzyme-like activity, have been activated with tumor microenvironment (TME) endogenous stimulators. Compared with previous nanomaterials, nanozymes combined with multi-enzyme-like activities, multi-modal imaging methods, and multifunctional therapy platforms show tremendous advantages, conducting effective therapy. Given remarkable progr...
Source: European Journal of Medicinal Chemistry - June 9, 2022 Category: Chemistry Authors: Xiaoguang Zhu Na Xu Lijing Zhang Dongmei Wang Peng Zhang Source Type: research

Expansion of the S-CN-DABO scaffold to exploit the impact on inhibitory activities against the non-nucleoside HIV-1 reverse transcriptase
Eur J Med Chem. 2022 Jun 3;238:114512. doi: 10.1016/j.ejmech.2022.114512. Online ahead of print.ABSTRACTThe α-cyanoarylmethyl-3, 4-dihydropyrimidin-4(3H)-ones (S-CN-DABOs) were reported as a kind of reverse transcriptase inhibitors of human immunodeficiency virus type-1 (HIV-1) by our group in 2007. In this paper, we proposed to expand the S-CN-DABO scaffold to enrich the structure-activity relationship (SAR) of the phenyl ring that was predicted to be located in the W229 hydrophobic pocket. Thirty-nine S-CN-DABO derivatives were manufactured to explore the impact on inhibitory activities against the non-nucleoside HIV-1 ...
Source: European Journal of Medicinal Chemistry - June 9, 2022 Category: Chemistry Authors: Xu Ling Qing-Qing Hao Christophe Pannecouque Erik De Clercq Fen-Er Chen Source Type: research