Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker
In this study, we present a novel series of N-aroylated 5-methoxybenzothiophene-2-carboxamides (imides) as potent and selective Clk1/4 inhibitors. Potency of this series was found to be mainly dependent on the presence of an intramolecular H-bond between an ortho-methoxy group and the imide NH, that stabilizes a nearly coplanar conformation of high affinity to the ATP binding pocket(s) of Clk1/4. The two most potent hits in this series, compounds 20 (4-fluoro-2-methoxy) and 31 (5-chloro-2-methoxy) had cell free Clk1 IC50s of 4 and 9.7 nM, respectively, besides an unprecedented selectivity over Clk2 with 62- and 50-times hi...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Dalia S El-Gamil Ahmed K ElHady Po-Jen Chen Tsong-Long Hwang Ashraf H Abadi Mohammad Abdel-Halim Matthias Engel Source Type: research

Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader
Eur J Med Chem. 2022 May 19;238:114459. doi: 10.1016/j.ejmech.2022.114459. Online ahead of print.ABSTRACTAKT and associated signaling pathways have been recognized as promising therapeutic targets for decades, and growing evidence indicates that inhibition or degradation of cellular AKT are viable strategies to treat cancer. Guided by an in silico modeling approach for rational linker design and based on our previous work in this field, we herein efficiently synthesized a small group of cereblon-recruiting AKT PROTAC molecules and identified a highly potent AKT degrader B4. Compared to the existing AKT degraders, B4 has a ...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Cheng-Liang Zhu Xiaomin Luo Tian Tian Zijian Rao Hanlin Wang Zhesheng Zhou Tian Mi Danni Chen Yongjin Xu Yizhe Wu Jinxin Che Yubo Zhou Jia Li Xiaowu Dong Source Type: research

Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress
Eur J Med Chem. 2022 May 20;238:114464. doi: 10.1016/j.ejmech.2022.114464. Online ahead of print.ABSTRACTAlzheimer's disease is a chronic and progressive brain neurodegenerative disease affecting over 30 million people globally. Currently, no effective treatment is available due to multiple factors involved in the progression of AD. Given that the numerous AD-related targets in the disease network, the multi-target-directed ligands (MTDLs) strategy are considered as the promising strategy to treat AD. Herein, the multi-target compounds with/without ChEs are in clinical and in progress are reviewed. To further characterize ...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Zhipei Sang Keren Wang Jianghong Dong Lei Tang Source Type: research

Discovery of (2-(pyrrolidin-1-yl)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone as a novel potent tubulin depolymerizing and vascular disrupting agent
In this study, a series of 2-substituted thieno[3,2-d]pyrimidin-4-yl(3,4,5-trimethoxyphenyl)methanones were designed, synthesized and evaluated as novel anti-tubulin polymerization and vascular disrupting agents. A pyrrolidin-1-yl derivative, compound 20, exhibited strong antiproliferative activities (average IC50 = 13.4 nM) against four cancer cell lines. 20 also showed retained potency toward paclitaxel-resistant A549 cells. 20 could significantly inhibit tubulin polymerization with an IC50 of 1.6 μM. 20 displayed strong induction of G2/M arrest and apoptosis through the mitochondrial pathway. Dose-dependent suppression...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Chao Tian Meng Wang Xueqi Shi Xuanzhen Chen Xiaowei Wang Zhili Zhang Junyi Liu Source Type: research

Chemical space exploration around indolylarylsulfone scaffold led to a novel class of highly active HIV-1 NNRTIs with spiro structural features
Eur J Med Chem. 2022 May 20;238:114471. doi: 10.1016/j.ejmech.2022.114471. Online ahead of print.ABSTRACTTo thoroughly investigate the uncharted chemical space around the entrance channel of HIV-1 reverse transcriptase (RT) and to improve the physicochemical properties, we introduced different spiro ring structures with high Fsp3 values as linkers at indole-2-carboxamide, attaching to various terminal substituents to enhance the interactions with the entrance channel. All the newly designed and synthesized indolylarylsulfone (IAS) derivatives exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Shenghua Gao Yusen Cheng Shu Song Letian Song Fabao Zhao Shujing Xu Dongwei Kang Lin Sun Ping Gao Erik De Clercq Christophe Pannecouque Xinyong Liu Peng Zhan Source Type: research

A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma
Eur J Med Chem. 2022 May 26;238:114489. doi: 10.1016/j.ejmech.2022.114489. Online ahead of print.ABSTRACTHuman dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. As a result, the optimal compound A37 exhibited a potent hDHODH inhibitory activity with an IC50 value of 10.2 nM,...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Chungen Li Yue Zhou Jing Xu Xia Zhou Zongkai Huang Ting Zeng Xiaowei Yang Lei Tao Kun Gou Xi Zhong Qiang Chen Youfu Luo Yinglan Zhao Source Type: research

Improving the selectivity of 3-amidinophenylalanine-derived matriptase inhibitors
Eur J Med Chem. 2022 May 12;238:114437. doi: 10.1016/j.ejmech.2022.114437. Online ahead of print.ABSTRACTA rational structure-based approach was employed to develop novel 3-amidinophenylalanine-derived matriptase inhibitors with improved selectivity against thrombin and factor Xa. Of all 23 new derivatives, several monobasic inhibitors exhibit high matriptase affinities and strong selectivity against thrombin. Some inhibitors also possess selectivity against factor Xa, although less pronounced as found for thrombin. A crystal structure of a selective monobasic matriptase inhibitor in complex with matriptase and three cryst...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Oliver Pilgram Aline Keils Gerrit E Benary Janis M üller Stefan Merkl Sandrine Ngaha Simon Huber Florent Chevillard Anne Harbig Viktor Magdolen Andreas Heine Eva B öttcher-Friebertshäuser Torsten Steinmetzer Source Type: research

Synthetic derivatives of the antifungal drug ciclopirox are active against herpes simplex virus 2
Eur J Med Chem. 2022 May 14;238:114443. doi: 10.1016/j.ejmech.2022.114443. Online ahead of print.ABSTRACTWe previously showed that the anti-fungal drug ciclopirox olamine effectively inhibits replication of herpes simplex virus (HSV)-1 and HSV-2. Given the rise of HSV strains that are resistant to nucleos(t)ide analog treatment, as well as the incomplete efficacy of nucleos(t)ide analogs, new inhibitory compounds must be explored for potential use in the treatment of HSV infection. In the present study, we analyzed 44 compounds derived from the core structure of ciclopirox olamine for inhibitory activity against HSV. Thirt...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Maryam Zangi Katherine A Donald Andreu Gazquez Casals Abaigeal D Franson Alice J Yu Elise M Marker Molly E Woodson Scott D Campbell M Abdul Mottaleb Tanguturi Venkata Narayana Hajay Kumar Makala Shakar Reddy Lingala Vijaya Raghava Reddy Subir Kumar Sadhuk Source Type: research

The structure-based design of peptidomimetic inhibitors against SARS-CoV-2 3C like protease as Potent anti-viral drug candidate
Eur J Med Chem. 2022 May 13;238:114458. doi: 10.1016/j.ejmech.2022.114458. Online ahead of print.ABSTRACTSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), as the pathogen of coronavirus disease 2019 (COVID-19), has infected millions of people and took hundreds of thousands of lives. Unfortunately, there is deficiency of effective medicines to prevent or treat COVID-19. 3C like protease (3CLPro) of SARS-CoV-2 is essential to the viral replication and transcription, and is an attractive target to develop anti-SARS-CoV-2 agents. Targeting on the 3CLPro, we screened our protease inhibitor library and obtained compo...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Hao Wang Rongjuan Pei Xin Li Weilong Deng Shuai Xing Yanan Zhang Chen Zhang Shuai He Hao Sun Shuqi Xiao Jin Xiong Yecheng Zhang Xinwen Chen Yaxin Wang Yu Guo Bo Zhang Luqing Shang Source Type: research

Design, synthesis of DNA-interactive 4-thiazolidinone-based indolo-/pyrroloazepinone conjugates as potential cytotoxic and topoisomerase I inhibitors
Eur J Med Chem. 2022 May 18;238:114465. doi: 10.1016/j.ejmech.2022.114465. Online ahead of print.ABSTRACTWith the rising cancer incidence and mortality globally, there is a prerequisite for effective design strategies towards the discovery of newer small molecular entities in chemotherapy. Hence, a series of new thiazolidinone-based indolo-/pyrroloazepinone conjugates was designed, synthesized via molecular hybridization, and evaluated for their in vitro cytotoxicity potential and DNA topoisomerase I and II inhibition. Among this series, conjugate 11g emerged as the most active compound with an IC50 value of 1.24 μM again...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Manasa Kadagathur Sandip Patra Geetanjali Devabattula Joel George Regur Phanindranath Arbaz Sujat Shaikh Dilep Kumar Sigalapalli Chandraiah Godugu Narayana Nagesh Neelima D Tangellamudi Nagula Shankaraiah Source Type: research

Development of sulfonamide-based NLRP3 inhibitors: Further modifications and optimization through structure-activity relationship studies
Eur J Med Chem. 2022 May 21;238:114468. doi: 10.1016/j.ejmech.2022.114468. Online ahead of print.ABSTRACTNLRP3 inflammasome dysregulation has been observed in many human diseases including neurodegenerative disorders. Thus, development of small molecule inhibitors targeting this protein complex represents a promising strategy to achieve disease intervention. In our continuing efforts to develop NLRP3 inhibitors, a recently identified lead inhibitor, YQ128, was further modified and optimized. The structure-activity relationship studies of this lead compound suggested its flexibility for structural modifications while the su...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Yiming Xu Yulong Xu Hallie Blevins Chunqing Guo Savannah Biby Xiang-Yang Wang Changning Wang Shijun Zhang Source Type: research

Selective inhibition of histone deacetylase 3 by novel hydrazide based small molecules as therapeutic intervention for the treatment of cancer
Eur J Med Chem. 2022 May 18;238:114470. doi: 10.1016/j.ejmech.2022.114470. Online ahead of print.ABSTRACTA promising hydrazide based small molecule lead as a potent and selective histone deacetylase 3 (HDAC3) inhibitor has been developed from a small series of synthesized novel chemical entities. The lead compound (4e) displayed high HDAC3 inhibitory potency (IC50 = 15.41 nM) and a minimum of 18-fold selectivity over other HDAC isoforms. It also exhibited potent cytotoxicity against several cancer cell lines with minimal toxicity against normal cell lines tested. Compound 4e also enhanced acetylation levels on H3K9, H4K12 ...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Sravani Pulya Tarun Patel Milan Paul Nilanjan Adhikari Suvankar Banerjee Ganesh Routholla Swati Biswas Tarun Jha Balaram Ghosh Source Type: research

Ring replacement recommender: Ring modifications for improving biological activity
Eur J Med Chem. 2022 May 23;238:114483. doi: 10.1016/j.ejmech.2022.114483. Online ahead of print.ABSTRACTAnalysis of structure-activity data from a large corpus of medicinal chemistry literature identified a set of ring replacements that have a significant chance of improved biological activity. A database of these replacements for 245 common heterocyclic rings is provided. Based on the analysis of the whole data set, 80 diverse substituted rings are suggested for use in an early stage of hit optimization and in the design of focused libraries with the goal to explore structure-activity relationships and quickly improve th...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Peter Ertl Eva Altmann Sophie Racine Richard Lewis Source Type: research

Ruthenium(II) complexes targeting membrane as biofilm disruptors and resistance breakers in Staphylococcus aureus bacteria
Eur J Med Chem. 2022 May 21;238:114485. doi: 10.1016/j.ejmech.2022.114485. Online ahead of print.ABSTRACTThe development of ruthenium-based complexes or antimicrobial peptides are identified as a promising strategy for combating drug-resistant bacteria. In this work, four biphenyl-based antibacterial ruthenium complexes by targeting membrane integrity, which act as antimicrobial peptides mimics, were designed and synthesized. In vitro antimicrobial screening demonstrated that four complexes could absolutely inhibit the growth of Staphylococcus aureus (S. aureus) with MIC values ranging from 15.6 to 100 μg/mL. The most act...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Liqiang Wang Lianghong Liu Xuerong Wang Yanhui Tan Xuemin Duan Chunyan Zhang Jianxin Cheng Yanshi Xiong Guijuan Jiang Jintao Wang Xiangwen Liao Source Type: research

Small molecules targeting cGAS-STING pathway for autoimmune disease
Eur J Med Chem. 2022 May 20;238:114480. doi: 10.1016/j.ejmech.2022.114480. Online ahead of print.ABSTRACTAutoimmune diseases represent a class of over 80 illnesses with high incidence and prevalence and share a common pathogenesis of immune system disorders and self-attack. Over the past decade, extensive studies have demonstrated that imbalance of cGAS-STING mediated innate immune signaling is closely involved in autoimmune diseases. Over-activation of cGAS-STING pathway by mutations of STING or several exonucleases can cause accumulation of interferon and systemic inflammation. Therefore, suppression of the upregulated c...
Source: European Journal of Medicinal Chemistry - May 31, 2022 Category: Chemistry Authors: Jiannan Zhao Ruoxuan Xiao Ruoqing Zeng Ende He Ao Zhang Source Type: research