Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity
This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Seyed-Omar Zaraei Nour N Al-Ach Hanan S Anbar Randa El-Gamal Hamadeh Tarazi Rimas T Tokatly Rawan R Kalla Mouna A Munther Marwa M Wahba Aya M Alshihabi Mahmoud K Shehata Rawan M Sbenati Afnan I Shahin Raafat El-Awady Taleb H Al-Tel Mohammed I El-Gamal Source Type: research

Dual-functional antitumor conjugates improving the anti-metastasis effect of combretastatin A4 by targeting tubulin polymerization and matrix metalloproteinases
This study prepared different novel conjugates containing tubulin and MMP inhibitors and assessed their anticancer effects. Typically, the conjugate 15g, which contained combretastatin A4 (CA4) and 2-(4-((diethoxyphosphono)(o-tolyl)methylamino)phenyl)acetic acid (19g) connected by an ester bond, showed the maximum effect against proliferation. Particularly, the conjugate yielded a reduced IC50 value of 0.05 μM in controlling the proliferation of HepG2 cells compared to CA4 alone (0.09 μM). Systematic research indicated that 15g suppressed tubulin polymerization, induced cell cycle arrest at the G2/M phase, led to reactiv...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Limin Yang Xin Ma Kerong Guo Jian Li Chong Zhang Liqiang Wu Source Type: research

Design, synthesis, and biological evaluation of trizole-based heteroaromatic derivatives as Bcr-Abl kinase inhibitors
Eur J Med Chem. 2022 May 6;238:114425. doi: 10.1016/j.ejmech.2022.114425. Online ahead of print.ABSTRACTBcr-Abl is a key driver in the pathophysiology of CML. Broadening the chemical diversity of Bcr-Abl kinase inhibitors to overcome drug resistance is a current medical demand for CML treatment. As a continuation to our research, a series of compounds with heteroaromatics-trizole scaffold as hinge binding moiety (HBM) were developed as Bcr-Abl inhibitors based on in silico modeling analysis. Biological results indicated that these compounds exhibited a significantly enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Xiaoyan Pan Nanxin Liu Yuying Liu Qingqing Zhang Kai Wang Xueying Liu Jie Zhang Source Type: research

Design and synthesis of harmiquins, harmine and chloroquine hybrids as potent antiplasmodial agents
Eur J Med Chem. 2022 Apr 30;238:114408. doi: 10.1016/j.ejmech.2022.114408. Online ahead of print.ABSTRACTMalaria remains one of the major health problems worldwide. The lack of an effective vaccine and the increasing resistance of Plasmodium to the approved antimalarial drugs demands the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Harmiquins represent hybrids that combine two moieties with different mechanisms of antiplasmodial activity in one molecule, i.e., a chloroquine (CQ) scaffold, known to inhibit heme polymerization and a β-carboline ring capable of binding to...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Goran Poje Lais Pessanha de Carvalho Jana Held Diana Moita Miguel Prud êncio Ivana Perkovi ć Tana Tandari ć Robert Vianello Zrinka Raji ć Source Type: research

Azetidin-2-one-based small molecules as dual hHDAC6/HDAC8 inhibitors: Investigation of their mechanism of action and impact of dual inhibition profile on cell viability
Eur J Med Chem. 2022 May 1;238:114409. doi: 10.1016/j.ejmech.2022.114409. Online ahead of print.ABSTRACTThe search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HDAC8 is an epigenetic eraser, unique HDAC-class I member that displays some aminoacidic similarity to HDAC6. New polypharmacological agents for cancer treatment, based on a dual...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Stefano Federico Tuhina Khan Anna Fontana Simone Brogi Rosaria Benedetti Federica Sarno Gabriele Carullo Alex Pezzotta Akella Prasanth Saraswati Eugenia Passaro Luca Pozzetti Alessandro Papa Nicola Relitti Sandra Gemma Stefania Butini Anna Pistocchi Anna Source Type: research

Development of 4-((3-oxo-3-phenylpropyl)amino)benzenesulfonamide derivatives utilizing tail/dual-tail approaches as novel carbonic anhydrase inhibitors
Eur J Med Chem. 2022 Apr 27;238:114412. doi: 10.1016/j.ejmech.2022.114412. Online ahead of print.ABSTRACTIn the current work, we adopted the tail/dual tail approaches to design and synthesize the benzenesulfonamide derivatives 6a-b, 8, 10a-b, 12a-b, 14, and 16 as new SLC-0111 analogs endowed with carbonic anhydrase (CA) inhibitory activity. All the prepared benzenesulfonamide derivatives were tested for their inhibitory action towards hCA isoforms; hCA I, II, IX, and XII. The results revealed their ability to affect the examined isoforms in variable degrees with KI ranges: 49.3-6459 nM for CA I, 5.1-4171 nM for CA II, 9.4-...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Mostafa M Elbadawi Wagdy M Eldehna Alessio Nocentini Warda R Somaa Sara T Al-Rashood Eslam B Elkaeed Mahmoud A El Hassab Hatem A Abdel-Aziz Claudiu T Supuran Mohamed Fares Source Type: research

The progress of small-molecules and degraders against BCR-ABL for the treatment of CML
Eur J Med Chem. 2022 May 6;238:114442. doi: 10.1016/j.ejmech.2022.114442. Online ahead of print.ABSTRACTChronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address t...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: You-Lu Pan Shen-Xin Zeng Rong-Rong Hao Mei-Hao Liang Zheng-Rong Shen Wen-Hai Huang Source Type: research

Identification, optimization, and biological evaluation of 3-O- β-chacotriosyl ursolic acid derivatives as novel SARS-CoV-2 entry inhibitors by targeting the prefusion state of spike protein
This study offers a set of novel SARS-CoV-2 fusion inhibitors against SARS-CoV-2 and its variants based on the 3-O-β-chacotriosyl UA skeleton.PMID:35551037 | DOI:10.1016/j.ejmech.2022.114426 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Hui Li Chen Cheng Shanshan Shi Yan Wu Yongfeng Gao Zhihao Liu Mingjian Liu Zhaodong Li Lijian Huo Xiapyan Pan Shuwen Liu Gaopeng Song Source Type: research

Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity
This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Seyed-Omar Zaraei Nour N Al-Ach Hanan S Anbar Randa El-Gamal Hamadeh Tarazi Rimas T Tokatly Rawan R Kalla Mouna A Munther Marwa M Wahba Aya M Alshihabi Mahmoud K Shehata Rawan M Sbenati Afnan I Shahin Raafat El-Awady Taleb H Al-Tel Mohammed I El-Gamal Source Type: research

Dual-functional antitumor conjugates improving the anti-metastasis effect of combretastatin A4 by targeting tubulin polymerization and matrix metalloproteinases
This study prepared different novel conjugates containing tubulin and MMP inhibitors and assessed their anticancer effects. Typically, the conjugate 15g, which contained combretastatin A4 (CA4) and 2-(4-((diethoxyphosphono)(o-tolyl)methylamino)phenyl)acetic acid (19g) connected by an ester bond, showed the maximum effect against proliferation. Particularly, the conjugate yielded a reduced IC50 value of 0.05 μM in controlling the proliferation of HepG2 cells compared to CA4 alone (0.09 μM). Systematic research indicated that 15g suppressed tubulin polymerization, induced cell cycle arrest at the G2/M phase, led to reactiv...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Limin Yang Xin Ma Kerong Guo Jian Li Chong Zhang Liqiang Wu Source Type: research

Design, synthesis, and biological evaluation of trizole-based heteroaromatic derivatives as Bcr-Abl kinase inhibitors
Eur J Med Chem. 2022 May 6;238:114425. doi: 10.1016/j.ejmech.2022.114425. Online ahead of print.ABSTRACTBcr-Abl is a key driver in the pathophysiology of CML. Broadening the chemical diversity of Bcr-Abl kinase inhibitors to overcome drug resistance is a current medical demand for CML treatment. As a continuation to our research, a series of compounds with heteroaromatics-trizole scaffold as hinge binding moiety (HBM) were developed as Bcr-Abl inhibitors based on in silico modeling analysis. Biological results indicated that these compounds exhibited a significantly enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in...
Source: European Journal of Medicinal Chemistry - May 13, 2022 Category: Chemistry Authors: Xiaoyan Pan Nanxin Liu Yuying Liu Qingqing Zhang Kai Wang Xueying Liu Jie Zhang Source Type: research

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis
In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1β and TNF-α. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.PMID:35544982 | DOI:10.1016/j.ejmech.2022.114423 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 11, 2022 Category: Chemistry Authors: Xuetao Chen Fanying Meng Jingtian Zhang Zijian Zhang Xuan Ye Weikun Zhang Yuanyuan Tong Xinrui Ji Rujun Xu Xiao-Li Xu Qi-Dong You Zheng-Yu Jiang Source Type: research

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis
In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1β and TNF-α. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.PMID:35544982 | DOI:10.1016/j.ejmech.2022.114423 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 11, 2022 Category: Chemistry Authors: Xuetao Chen Fanying Meng Jingtian Zhang Zijian Zhang Xuan Ye Weikun Zhang Yuanyuan Tong Xinrui Ji Rujun Xu Xiao-Li Xu Qi-Dong You Zheng-Yu Jiang Source Type: research

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis
In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1β and TNF-α. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.PMID:35544982 | DOI:10.1016/j.ejmech.2022.114423 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 11, 2022 Category: Chemistry Authors: Xuetao Chen Fanying Meng Jingtian Zhang Zijian Zhang Xuan Ye Weikun Zhang Yuanyuan Tong Xinrui Ji Rujun Xu Xiao-Li Xu Qi-Dong You Zheng-Yu Jiang Source Type: research

Novel hybrid pyrrolidinedione-thiazolidinones as potential anticancer agents: Synthesis and biological evaluation
Eur J Med Chem. 2022 May 2;238:114422. doi: 10.1016/j.ejmech.2022.114422. Online ahead of print.ABSTRACTA series of novel pyrrolidinedione-thiazolidinones was synthesized and subjected to physico-chemical characteristics. They were screened on a panel of cell lines representing different types of cancer, as well as normal human keratynocytes and lymphocytes of peripheral human blood. High antiproliferative activity of 1-(4-chlorophenyl)- and 1-(4-hydroxyphenyl)-3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}-1-(4-hydroxyphenyl)-pyrrolidine-2,5-diones 2a and 2b was revealed along wit...
Source: European Journal of Medicinal Chemistry - May 9, 2022 Category: Chemistry Authors: Nataliya Finiuk Anna Kryshchyshyn-Dylevych Serhii Holota Olga Klyuchivska Andriy Kozytskiy Olexandr Karpenko Nazar Manko Iryna Ivasechko Rostyslav Stoika Roman Lesyk Source Type: research