New TRPM8 blockers exert anticancer activity over castration-resistant prostate cancer models
Eur J Med Chem. 2022 May 12;238:114435. doi: 10.1016/j.ejmech.2022.114435. Online ahead of print.ABSTRACTTRPM8 has recently emerged as a druggable target in prostate cancer (PC) and TRPM8 modulators have been proposed as potential anticancer agents in this pathology. We have recently demonstrated their effectiveness in a castration-resistant prostate cancer (CRPC) model that is usually resistant to androgen deprivation therapy (ADT) and is considered the most aggressive form of PC. This is why the discovery of selective, effective, and potent TRPM8 modulators would improve the molecular arsenal in support of PC standard-of...
Source: European Journal of Medicinal Chemistry - May 22, 2022 Category: Chemistry Authors: Veronica Di Sarno Pia Giovannelli Alicia Medina-Peris Tania Ciaglia Marzia Di Donato Simona Musella Gianluigi Lauro Vincenzo Vestuto Gerardina Smaldone Francesca Di Matteo Giuseppe Bifulco Gabriella Castoria Antimo Migliaccio Asia Fernandez-Carvajal Pietr Source Type: research

Synthesis of 10,10'-bis(trifluoromethyl) marinopyrrole A derivatives and evaluation of their antiviral activities in vitro
Eur J Med Chem. 2022 May 6;238:114436. doi: 10.1016/j.ejmech.2022.114436. Online ahead of print.ABSTRACTFlavivirus and enterovirus can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases or even death. Since effective vaccine is currently unavailable against most of these deadly viruses, antiviral chemical drugs remain in urgent need. To meet this unmet demand, we developed a series of 10,10'-bis(trifluoromethyl) marinopyrrole A derivates bearing various substituents at C5'-positions, which exhibited impressive in vitro activities against flaviviruses (ZIKV, DENV, YFV, JEV) and ente...
Source: European Journal of Medicinal Chemistry - May 22, 2022 Category: Chemistry Authors: Yaxin Xiao Jingjing Yang Liangjing Zou Pingzhou Wu Wei Li Yunzheng Yan Yuexiang Li Song Li Hao Song Wu Zhong Yong Qin Source Type: research

Novel flavonoid hybrids as potent antiviral agents against hepatitis A: Design, synthesis and biological evaluation
Eur J Med Chem. 2022 May 14;238:114452. doi: 10.1016/j.ejmech.2022.114452. Online ahead of print.ABSTRACTTwo series of flavonoid hybrids, totaling 42 compounds, were designed, synthesized and evaluated to develop antiviral compounds effective against hepatitis A virus (HAV). A recombinant viral screening system revealed that most of the synthesized derivatives exhibited significant anti-HAV activity, and compounds B2, B3, B5 and B27 were identified as potential inhibitors of HAV. Post-treatment of cells with B2, B3, B5 and B27 after HAV infection strongly suppressed HAV infection, whereas pretreatment or simultaneous treat...
Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Shaochun Shi Xin Zheng Ryosuke Suzuki Ziyue Li Tomoyuki Shiota Jiayin Wang Asuka Hirai-Yuki Qingbo Liu Masamichi Muramatsu Shao-Jiang Song Source Type: research

Synthesis and Structure-Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold
In this study, we describe a medicinal chemistry campaign to identify a CDK11 inhibitor. Employing a promising but nonselective CDK11-targeting scaffold (JWD-047), extensive structure-guided medicinal chemistry modifications led to the identification of ZNL-05-044. A combination of biochemical evaluations and NanoBRET cellular assays for target engagement guided the SAR towards a 2,4-diaminothiazoles CDK11 probe with significantly improved kinome-wide selectivity over JWD-047. CDK11 inhibition with ZNL-05-044 leads to G2/M cell cycle arrest, consistent with prior work evaluating OTS964, and impacts CDK11-dependent mRNA spl...
Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Zhengnian Li Ryosuke Ishida Yan Liu Jinhua Wang Yina Li Yang Gao Jie Jiang Jianwei Che Jason M Sheltzer Matthew B Robers Tinghu Zhang Kenneth D Westover Behnam Nabet Nathanael S Gray Source Type: research

Discovery of a potent, selective and cell active inhibitor of m < sup > 6 < /sup > A demethylase ALKBH5
Eur J Med Chem. 2022 May 11;238:114446. doi: 10.1016/j.ejmech.2022.114446. Online ahead of print.ABSTRACTAlkB homolog 5 (ALKBH5) is an RNA m6A demethylase involved in the regulation of genes transcription, translation and metabolism and has been considered as a promising therapeutic target for various human diseases, especially cancers. However, there is still a lack of potent and selective ALKBH5 inhibitors. Herein, we report a new class of ALKBH5 inhibitors containing the 1-aryl-1H-pyrazole scaffold, which were obtained through fluorescence polarization-based screening, structural optimization and structure-activity rela...
Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Zhen Fang Bo Mu Yang Liu Nihong Guo Liang Xiong Yinping Guo Anjie Xia Rong Zhang Hailin Zhang Rui Yao Yan Fan Linli Li Shengyong Yang Rong Xiang Source Type: research

Emerging impact of triazoles as anti-tubercular agent
Eur J Med Chem. 2022 May 13;238:114454. doi: 10.1016/j.ejmech.2022.114454. Online ahead of print.ABSTRACTTuberculosis, a disease of poverty is a communicable infection with a reasonably high mortality rate worldwide. 10 Million new cases of TB were reported with approx 1.4 million deaths in the year 2019. Due to the growing number of drug-sensitive and drug-resistant tuberculosis cases, there is a vital need to develop new and effective candidates useful to combat this deadly disease. Despite tremendous efforts to identify a mechanism-based novel antitubercular agent, only a few have entered into clinical trials in the las...
Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Anindra Sharma Anand K Agrahari Sanchayita Rajkhowa Vinod K Tiwari Source Type: research

New peptidomimetic rhodesain inhibitors with improved selectivity towards human cathepsins
Eur J Med Chem. 2022 May 14;238:114460. doi: 10.1016/j.ejmech.2022.114460. Online ahead of print.ABSTRACTParasitic cysteine proteases such as rhodesain (TbCatL) from Trypanosoma brucei rhodesiense are relevant targets for developing new potential drugs against parasitic diseases (e. g. Human African Trypanosomiasis). Designing selective inhibitors for parasitic cathepsins can be challenging as they share high structural similarities with human cathepsins. In this paper, we describe the development of novel peptidomimetic rhodesain inhibitors by applying a structure-based de novo design approach and molecular docking protoc...
Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Sascha Jung Natalie Fuchs Christoph Grathwol Ute A Hellmich Annika Wagner Erika Diehl Thomas Willmes Christoph Sotriffer Tanja Schirmeister Source Type: research

Identification and development of a series of disubstituted piperazines for the treatment of Chagas disease
Eur J Med Chem. 2022 May 6;238:114421. doi: 10.1016/j.ejmech.2022.114421. Online ahead of print.ABSTRACTApproximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacement...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Kate McGonagle Gary J Tarver Juan Cantizani Ignacio Cotillo Peter G Dodd Liam Ferguson Ian H Gilbert Maria Marco Tim Miles Claire Naylor Maria Osuna-Cabello Christy Paterson Kevin D Read Erika G Pinto Jennifer Riley Paul Scullion Yoko Shishikura Frederick Source Type: research

Design, synthesis and antitumour activity of novel 5(6)-amino-benzimidazolequinones containing a fused morpholine
Eur J Med Chem. 2022 May 11;238:114420. doi: 10.1016/j.ejmech.2022.114420. Online ahead of print.ABSTRACTBased on the previous synthesis of tetracyclic and tricyclic benzimidazoles starting from 1,4:3,6-dianhydro-d-fructose and o-phenylenediamines, a series of 5(6)-amino substituted tetracyclic and tricyclic benzimidazolequinones were obtained through the oxidation of 4,7-dimethoxy-benzimidazole analogues with bis(trifluoroacetoxy)iodobenzene (PIFA) and subsequent substitution with various aliphatic and aromatic amines. Biological evaluations of the target benzimidazolequinones indicated that all the arylamino-substituted ...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Haixia Wang Yao Meng Jing Yang Hao Huang Yifan Zhao Chuantao Zhu Cong Wang Feng-Wu Liu Source Type: research

Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686
Eur J Med Chem. 2022 May 12;238:114455. doi: 10.1016/j.ejmech.2022.114455. Online ahead of print.ABSTRACTEpidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFRL858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Qinlan Li Qian Guo Shuyi Wang Shanhe Wan Zhonghuang Li Jiajie Zhang Xiaoyun Wu Source Type: research

Identification and development of a series of disubstituted piperazines for the treatment of Chagas disease
Eur J Med Chem. 2022 May 6;238:114421. doi: 10.1016/j.ejmech.2022.114421. Online ahead of print.ABSTRACTApproximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacement...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Kate McGonagle Gary J Tarver Juan Cantizani Ignacio Cotillo Peter G Dodd Liam Ferguson Ian H Gilbert Maria Marco Tim Miles Claire Naylor Maria Osuna-Cabello Christy Paterson Kevin D Read Erika G Pinto Jennifer Riley Paul Scullion Yoko Shishikura Frederick Source Type: research

Design, synthesis and antitumour activity of novel 5(6)-amino-benzimidazolequinones containing a fused morpholine
Eur J Med Chem. 2022 May 11;238:114420. doi: 10.1016/j.ejmech.2022.114420. Online ahead of print.ABSTRACTBased on the previous synthesis of tetracyclic and tricyclic benzimidazoles starting from 1,4:3,6-dianhydro-d-fructose and o-phenylenediamines, a series of 5(6)-amino substituted tetracyclic and tricyclic benzimidazolequinones were obtained through the oxidation of 4,7-dimethoxy-benzimidazole analogues with bis(trifluoroacetoxy)iodobenzene (PIFA) and subsequent substitution with various aliphatic and aromatic amines. Biological evaluations of the target benzimidazolequinones indicated that all the arylamino-substituted ...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Haixia Wang Yao Meng Jing Yang Hao Huang Yifan Zhao Chuantao Zhu Cong Wang Feng-Wu Liu Source Type: research

Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686
Eur J Med Chem. 2022 May 12;238:114455. doi: 10.1016/j.ejmech.2022.114455. Online ahead of print.ABSTRACTEpidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFRL858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Qinlan Li Qian Guo Shuyi Wang Shanhe Wan Zhonghuang Li Jiajie Zhang Xiaoyun Wu Source Type: research

Structure-based discovery and development of novel O-GlcNAcase inhibitors for the treatment of Alzheimer's disease
Eur J Med Chem. 2022 May 13;238:114444. doi: 10.1016/j.ejmech.2022.114444. Online ahead of print.ABSTRACTThe neurofibrillary tangles (NFTs) formed from hyperphosphorylation of tau protein are closely associated with Alzheimer's disease (AD). O-GlcNAcylation of tau can negatively regulate hyperphosphorylation and the O-GlcNAcase (OGA) catalyzes the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from tau protein. Therefore, preventing tau hyperphosphorylation by increasing the levels of tau O-GlcNAcylation via OGA inhibitors could be a promising approach. Based on Thiamet-G, a potent OGA inhibitor, and its binding mod...
Source: European Journal of Medicinal Chemistry - May 19, 2022 Category: Chemistry Authors: Xiaoli Li Jinhe Han Sheshurao Bujaranipalli Jie He Eun Young Kim Hee Kim Jae Hong Im Won-Jea Cho Source Type: research

Structure-based discovery and development of novel O-GlcNAcase inhibitors for the treatment of Alzheimer's disease
Eur J Med Chem. 2022 May 13;238:114444. doi: 10.1016/j.ejmech.2022.114444. Online ahead of print.ABSTRACTThe neurofibrillary tangles (NFTs) formed from hyperphosphorylation of tau protein are closely associated with Alzheimer's disease (AD). O-GlcNAcylation of tau can negatively regulate hyperphosphorylation and the O-GlcNAcase (OGA) catalyzes the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from tau protein. Therefore, preventing tau hyperphosphorylation by increasing the levels of tau O-GlcNAcylation via OGA inhibitors could be a promising approach. Based on Thiamet-G, a potent OGA inhibitor, and its binding mod...
Source: European Journal of Medicinal Chemistry - May 19, 2022 Category: Chemistry Authors: Xiaoli Li Jinhe Han Sheshurao Bujaranipalli Jie He Eun Young Kim Hee Kim Jae Hong Im Won-Jea Cho Source Type: research