Seeking heterocyclic scaffolds as antivirals against dengue virus
Eur J Med Chem. 2022 Jul 3;240:114576. doi: 10.1016/j.ejmech.2022.114576. Online ahead of print.ABSTRACTDengue is one of the most typical viral infection categorized in the Neglected Tropical Diseases (NTDs). It is transmitted via the female Aedes aegypti mosquito to humans and majorly puts risk to the lives of more than half of the world. Recent advancements in medicinal chemistry have led to the design and development of numerous potential heterocyclic scaffolds as antiviral drug candidates for the inhibition of the dengue virus (DENV). Thus, in this review, we have discussed the significance of inhibitory and antiviral ...
Source: European Journal of Medicinal Chemistry - July 11, 2022 Category: Chemistry Authors: Soumik De Bari Aamna Raghaba Sahu Sagarika Parida Santosh Kumar Behera Aritra Kumar Dan Source Type: research

Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani
Eur J Med Chem. 2022 Jul 1;240:114577. doi: 10.1016/j.ejmech.2022.114577. Online ahead of print.ABSTRACTVisceral leishmaniasis is a potentially fatal disease caused by the parasitic protists, Leishmania donovani and L. infantum. Current treatments remain unsuitable due to cost, the need for hospitalization, variable efficacy against different species, toxicity and emerging resistance. Herein, we report the SAR exploration of the novel hit 4-Fluoro-N-(5-(4-methoxyphenyl)-1-methyl-1H-imidazole-2-yl)benzamide [1] previously identified from a high throughput screen against Trypanosoma brucei, Trypanosoma cruzi and Leishmania d...
Source: European Journal of Medicinal Chemistry - July 10, 2022 Category: Chemistry Authors: Nicole McNamara Eleanor Saunders Swapna Varghese Rebecca Zheng Kaylene Simpson Devika M Varma Monica M Johnson M Shamim Hasan Zahid Eric M Bachelder Kristy M Ainslie Joo Hwan No Dahae Koh David Shum Nirmal Das Binita Patra Jayasree Roy Arindam Talukdar Di Source Type: research

Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani
Eur J Med Chem. 2022 Jul 1;240:114577. doi: 10.1016/j.ejmech.2022.114577. Online ahead of print.ABSTRACTVisceral leishmaniasis is a potentially fatal disease caused by the parasitic protists, Leishmania donovani and L. infantum. Current treatments remain unsuitable due to cost, the need for hospitalization, variable efficacy against different species, toxicity and emerging resistance. Herein, we report the SAR exploration of the novel hit 4-Fluoro-N-(5-(4-methoxyphenyl)-1-methyl-1H-imidazole-2-yl)benzamide [1] previously identified from a high throughput screen against Trypanosoma brucei, Trypanosoma cruzi and Leishmania d...
Source: European Journal of Medicinal Chemistry - July 10, 2022 Category: Chemistry Authors: Nicole McNamara Eleanor Saunders Swapna Varghese Rebecca Zheng Kaylene Simpson Devika M Varma Monica M Johnson M Shamim Hasan Zahid Eric M Bachelder Kristy M Ainslie Joo Hwan No Dahae Koh David Shum Nirmal Das Binita Patra Jayasree Roy Arindam Talukdar Di Source Type: research

Corrigendum to "Design and synthesis of highly TRAIL expression HDAC inhibitors based on ONC201 to promote apoptosis of colorectal cancer" [Eur. J. Med. Chem. 238 (2022) 1-20/114484]
Eur J Med Chem. 2022 Jul 7;240:114568. doi: 10.1016/j.ejmech.2022.114568. Online ahead of print.NO ABSTRACTPMID:35809536 | DOI:10.1016/j.ejmech.2022.114568 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - July 9, 2022 Category: Chemistry Authors: Hao Cui Zan Hu Kang Yang Jingkun Huang Yichao Wu Quanwei Chen Ran Wei Penfeng Wang Hui Wang Hongmei Li Yadong Chen Tao Lu Yuqin Yao Yong Zhu Source Type: research

Corrigendum to "Design and synthesis of highly TRAIL expression HDAC inhibitors based on ONC201 to promote apoptosis of colorectal cancer" [Eur. J. Med. Chem. 238 (2022) 1-20/114484]
Eur J Med Chem. 2022 Jul 6;240:114568. doi: 10.1016/j.ejmech.2022.114568. Online ahead of print.NO ABSTRACTPMID:35809536 | DOI:10.1016/j.ejmech.2022.114568 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - July 9, 2022 Category: Chemistry Authors: Hao Cui Zan Hu Kang Yang Jingkun Huang Yichao Wu Quanwei Chen Ran Wei Penfeng Wang Hui Wang Hongmei Li Yadong Chen Tao Lu Yuqin Yao Yong Zhu Source Type: research

Design and synthesis of NAD(P)H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties
Eur J Med Chem. 2022 Jun 30;240:114575. doi: 10.1016/j.ejmech.2022.114575. Online ahead of print.ABSTRACTA series of NQO1 selectively activated prodrugs were designed and synthesized by introducing indolequinone moiety to the C-3, C-23 or C-28 position of 23-hydroxybetulinic acid (23-HBA) and its analogues. Among them, the representative compound 32j exhibited significant antiproliferative activities against NQO1-overexpressing HT-29 cells and A549 cells, with IC50 values of 1.87 and 2.36 μM, respectively, which were 20-30-fold more potent than those of parent compound 23-HBA. More importantly, it was demonstrated in the ...
Source: European Journal of Medicinal Chemistry - July 8, 2022 Category: Chemistry Authors: Huajian Zhu Lixue Lu Wenjian Zhu Yuchen Tan Yiping Duan Jie Liu Wencai Ye Zheying Zhu Jinyi Xu Shengtao Xu Source Type: research

Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives as RAF-MEK-ERK pathway signaling pathway blockers: Synthesis, cytotoxic activity, mechanistic investigation and structure-activity relationships
Eur J Med Chem. 2022 Jun 28;240:114579. doi: 10.1016/j.ejmech.2022.114579. Online ahead of print.ABSTRACTThe constitutive activation of ERK1/2 (RAF-MEK-ERK) signaling pathway has been widely observed in many types of tumors, and the blockade of ERK1/2 signaling pathway has been proved to reduce tumor growth. Therefore, ERK1/2 signaling pathway has become an interesting therapeutic target for cancer therapy. Despite the successful development of BRAF and MEK inhibitors in clinic treatment, resistance often appears to re-enhance ERK1/2 signaling. Here we report the design, synthesis, biological activity of a series of novel ...
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Qian Xie Yanni Shen Yanli Meng Jianhui Liang Jing Xu Shishao Liang Xiaoping Liu Yan Wang Chun Hu Source Type: research

Modulating the selectivity of inhibitors for prolyl oligopeptidase inhibitors and fibroblast activation protein- α for different indications
We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to one scaffold yielding new POP-selective inhibitors and a dual inhibitor equipotent to the only drug targeting FAP and POP that ever reached clinical trials.PMID:35797897 | DOI:10.1016/j.ejmech.2022.114543 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Jessica Plescia Damien H édou Maud Eva Pousse Anne Labarre Caroline Dufresne Anthony Mittermaier Nicolas Moitessier Source Type: research

Discovery of novel biphenyl-substituted pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with promising oral bioavailability
Eur J Med Chem. 2022 Jun 30;240:114581. doi: 10.1016/j.ejmech.2022.114581. Online ahead of print.ABSTRACTAdding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66, which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (E...
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Li-Min Zhao Shuai Wang Christophe Pannecouque Erik De Clercq Hu-Ri Piao Fen-Er Chen Source Type: research

Chalcone-amide, a privileged backbone for the design and development of selective SARS-CoV/SARS-CoV-2 papain-like protease inhibitors
Eur J Med Chem. 2022 Jul 3;240:114572. doi: 10.1016/j.ejmech.2022.114572. Online ahead of print.ABSTRACTThe newly emerged coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the COVID-19 pandemic, is the closest relative of SARS-CoV with high genetic similarity. The papain-like protease (PLpro) is an important SARS-CoV/SARS-CoV-2 nonstructural protein that plays a critical role in some infection processes such as the generation of the functional replication complex, maturation of crude polyproteins, and regulation of the host antiviral immune responses. Therefore, the research to discover S...
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Mehdi Valipour Source Type: research

Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors
Eur J Med Chem. 2022 Jul 1;240:114573. doi: 10.1016/j.ejmech.2022.114573. Online ahead of print.ABSTRACTA series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in ...
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Camille Hauguel Sarah Ducellier Olivier Provot Nada Ibrahim Diana Lamaa Coline Balcerowiak Boris Letribot Megane Nascimento Vincent Blanchard Laurie Askenatzis Helene Levaique J érôme Bignon Francesco Baschieri Cyril Bauvais Guillaume Bollot Dolor Renko Source Type: research

Discovery of fused benzimidazole-imidazole autophagic flux inhibitors for treatment of triple-negative breast cancer
Eur J Med Chem. 2022 Jun 26;240:114565. doi: 10.1016/j.ejmech.2022.114565. Online ahead of print.ABSTRACTTriple-negative breast cancer (TNBC) with the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 ptotein, is the highly aggressive subtype of breast cancer that exhibits poor prognosis and high tumor recurrence. It is vital to develop effective agents regulating the core molecular pathway of TNBC. Through a medium throughput screening and iterative medicinal chemistry optimization, we identified compound 7h as an autophagic flux inhibitor, which showed potent activities against human TNBC (MDA-MB-231...
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Dong-Lin Yang Ya-Jun Zhang Jie Lei Shi-Qiang Li Liu-Jun He Dian-Yong Tang Chuan Xu Ling-Tian Zhang Jingyuan Wen Hui-Kuan Lin Hong-Yu Li Zhong-Zhu Chen Zhi-Gang Xu Source Type: research

Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives as RAF-MEK-ERK pathway signaling pathway blockers: Synthesis, cytotoxic activity, mechanistic investigation and structure-activity relationships
Eur J Med Chem. 2022 Jun 28;240:114579. doi: 10.1016/j.ejmech.2022.114579. Online ahead of print.ABSTRACTThe constitutive activation of ERK1/2 (RAF-MEK-ERK) signaling pathway has been widely observed in many types of tumors, and the blockade of ERK1/2 signaling pathway has been proved to reduce tumor growth. Therefore, ERK1/2 signaling pathway has become an interesting therapeutic target for cancer therapy. Despite the successful development of BRAF and MEK inhibitors in clinic treatment, resistance often appears to re-enhance ERK1/2 signaling. Here we report the design, synthesis, biological activity of a series of novel ...
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Qian Xie Yanni Shen Yanli Meng Jianhui Liang Jing Xu Shishao Liang Xiaoping Liu Yan Wang Chun Hu Source Type: research

Modulating the selectivity of inhibitors for prolyl oligopeptidase inhibitors and fibroblast activation protein- α for different indications
We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to one scaffold yielding new POP-selective inhibitors and a dual inhibitor equipotent to the only drug targeting FAP and POP that ever reached clinical trials.PMID:35797897 | DOI:10.1016/j.ejmech.2022.114543 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Jessica Plescia Damien H édou Maud Eva Pousse Anne Labarre Caroline Dufresne Anthony Mittermaier Nicolas Moitessier Source Type: research

Discovery of novel biphenyl-substituted pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with promising oral bioavailability
Eur J Med Chem. 2022 Jun 30;240:114581. doi: 10.1016/j.ejmech.2022.114581. Online ahead of print.ABSTRACTAdding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66, which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (E...
Source: European Journal of Medicinal Chemistry - July 7, 2022 Category: Chemistry Authors: Li-Min Zhao Shuai Wang Christophe Pannecouque Erik De Clercq Hu-Ri Piao Fen-Er Chen Source Type: research