Design, synthesis, and biological evaluation of pyrrolopyrimidine derivatives as novel Bruton's tyrosine kinase (BTK) inhibitors
Eur J Med Chem. 2022 Jul 15;241:114611. doi: 10.1016/j.ejmech.2022.114611. Online ahead of print.ABSTRACTDeveloping Bruton's tyrosine kinase (BTK) inhibitors has become a significant focus in recent years because BTK inhibition is an effective approach for the treatment of B-cell malignancies. For covalent BTK inhibitors, low oral bioavailability and low kinase selectivity remain unaddressed issues; thus, more diverse inhibitors with both novel structures and selective on target binding profiles are still needed. Here, four key regions where inhibitors bind to BTK were identified by analyzing the existing crystal structure...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Minjian Yang Huimin Jiang Zhuo Yang Xue Liu Hanyu Sun Mengyao Hao Jinping Hu Xiaoguang Chen Jing Jin Xiaojian Wang Source Type: research

Novel fragment-derived colchicine-site binders as microtubule-destabilizing agents
Eur J Med Chem. 2022 Jul 16;241:114614. doi: 10.1016/j.ejmech.2022.114614. Online ahead of print.ABSTRACTMicrotubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments. Here, we sought to capitalize on this study with the aim to demonstrate that low affinity tubulin-bin...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Noelia Montel de la Roche Tobias M ühlethaler Rita Maria Concetta Di Martino Jose Antonio Ortega Dario Gioia Bibhas Roy Andrea E Prota Michel O Steinmetz Andrea Cavalli Source Type: research

Design, synthesis and antitumor evaluation of ATP dual-mimic 2,4-diarylaminopyrimidine and aminoindazole conjugates as potent anaplastic lymphoma kinase inhibitors
Eur J Med Chem. 2022 Jul 31;241:114626. doi: 10.1016/j.ejmech.2022.114626. Online ahead of print.ABSTRACTA series of hybrid anaplastic lymphoma kinase (ALK) inhibitors (Y1∼Y30) were designed by assembling aminoindazole of Entrectinib onto 2-position of 2,4-diarylaminopyrimidine (DAAP) fragment to serve as ATP dual-mimic agents. Under structure-based optimization, all conjugates were detected moderate to excellent cytotoxicity potency, among which the pyrrolidine analog Y28 exerted optimal antiproliferative effects on ALK-addicted cell lines with IC50 values below 20 nM. As a highly potent ALK inhibitor (ALKWT, IC50 = 1.6...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Jing Yang Deyi Ma Shuyu Liu Zehui Tan Ming Guo Zhi Cao Jiahao Zhang Xin Zhai Source Type: research

Discovery of 2,5-diphenyl-1,3,4-thiadiazole derivatives as HDAC inhibitors with DNA binding affinity
Eur J Med Chem. 2022 Jul 31;241:114634. doi: 10.1016/j.ejmech.2022.114634. Online ahead of print.ABSTRACTIncorporating a DNA-binding fragment in HDAC inhibitors has been proved to be an effective strategy for the treatment of hematologic malignancies by our group. However, similar to other approved HDAC inhibitors, their effects on solid tumor were poor. For this issue, a series of 2,5-diphenyl-1,3,4-thiadiazole hydroxamate derivatives were designed and synthesized as the HDAC inhibitors with DNA binding affinity. Among the target compounds, 4j not only bound with DNA effectively but also exhibited the most potent inhibito...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Chen Chen Hongrui Chu Anyang Wang Huanhuan Yin Yanqiao Gao Shuhua Liu Wei Li Leiqiang Han Source Type: research

A phthalocyanine-based photosensitizer for effectively combating triple negative breast cancer with enhanced photodynamic anticancer activity and immune response
Eur J Med Chem. 2022 Aug 1;241:114644. doi: 10.1016/j.ejmech.2022.114644. Online ahead of print.ABSTRACTAlthough photodynamic therapy (PDT) has attracted great interest, the photosensitizers in clinical had weak inhibition on metastasis and invasion of cancers. Additionally the immune response induced by PDT was insufficient to eradicate cancer. Herein, indoximod, an inhibitor of indoleamine 2,3-dioxygenase (IDO), is introduced to concatenate with zinc phthalocyanines (ZnPc) for effectively overcoming above inadequacy. Due to indoximod moiety, photosensitizer 1-MT-Pc can obtain enhanced intracellular uptake and high reacti...
Source: European Journal of Medicinal Chemistry - August 8, 2022 Category: Chemistry Authors: Kunshan Huang Meiqi Yan Han Zhang Jinping Xue Juanjuan Chen Source Type: research

Rational design of a trypanocidal peptide derived from Dinoponera quadriceps venom
Eur J Med Chem. 2022 Jul 31;241:114624. doi: 10.1016/j.ejmech.2022.114624. Online ahead of print.ABSTRACTChagas disease is caused by the parasite Trypanosoma cruzi and affects millions of people worldwide, having no effective cure. The main sanitary emergency is related to patients with chronic infection, which accumulate comorbidities causing patient death. However, actual chemotherapeutic treatments do not effectively address the chronic forms of the disease. Invertebrates are a relevant source of antimicrobial peptides (AMPs) as part of the innate immune system for their protection. The AMP M-PONTX-Dq3a, isolated from t...
Source: European Journal of Medicinal Chemistry - August 7, 2022 Category: Chemistry Authors: Mar ília Lopes Monteiro D ânya Bandeira Lima Katielle Albuquerque Freire Cibele Nicolaski Pedron Emanuel Paula Magalh ães Brenna Pinheiro Silva Alicia Bel én García-Jareño Cyntia Silva De Oliveira Jo ão Victor Serra Nunes Marcia Machado Marinho Ram Source Type: research

Synthesis and antiviral properties of biomimetic iminosugar-based nucleosides
Eur J Med Chem. 2022 Jul 19;241:114618. doi: 10.1016/j.ejmech.2022.114618. Online ahead of print.ABSTRACTHerein we report the synthesis, conformational analysis and the evaluation of the antiviral activity of six-membered nucleoside analogues having a piperidine ring as the preorganized (deoxy)ribose bioisostere. Mutagenic nucleobase-containing nucleosides 1 and 2 were obtained by appropriate manipulation of the well-known glycomimetic agent deoxynojirimycin as easily accessible starting material. In vitro assays revealed activity of 5-iododeoxyuridine analogue 1 against all DNA viruses tested. As suggested by DFT analysis...
Source: European Journal of Medicinal Chemistry - August 7, 2022 Category: Chemistry Authors: Maria De Fenza Anna Esposito Giovanni Talarico Graciela Andrei Robert Snoeck Daniele D'Alonzo Annalisa Guaragna Source Type: research

High ligand efficiency quinazoline compounds as novel A < sub > 2A < /sub > adenosine receptor antagonists
Eur J Med Chem. 2022 Jul 22;241:114620. doi: 10.1016/j.ejmech.2022.114620. Online ahead of print.ABSTRACTThe past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A2A receptor (A2AAR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A2AAR antagonists with high ligand efficiency. This class ...
Source: European Journal of Medicinal Chemistry - August 7, 2022 Category: Chemistry Authors: Rapha ël Bolteau Romain Duroux Am élie Laversin Brandon Vreulz Anna Shiriaeva Benjamin Stauch Gye Won Han Vadim Cherezov Nicolas Renault Am élie Barczyk S éverine Ravez Mathilde Coevoet Patricia Melnyk Maxime Liberelle Sa ïd Yous Source Type: research

Design, synthesis, and biological evaluation of novel 7-substituted 10,11-methylenedioxy-camptothecin derivatives against drug-resistant small-cell lung cancer in vitro and in vivo
Eur J Med Chem. 2022 Jul 20;241:114610. doi: 10.1016/j.ejmech.2022.114610. Online ahead of print.ABSTRACTA series of novel 7-substituted 10,11-methylenedioxy-camptothecin (FL118) derivatives were designed, synthesized, and biologically evaluated. All the FL118 analogues showed significant cytotoxic activities in vitro with IC50 values in the nanomolar range and were more potent than topotecan. The most active compound 9c exhibited more significant anti-tumor activity against small-cell lung cancer (NCI-H446, H69, drug-resistant H69AR cells, drug-resistant NCI-H446/Irinotecan cells and drug-resistant NCI-H446/EP cells) in v...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Guorui Zhang Ruijuan Yin Xiufei Dai Guanzhao Wu Xin Qi Rilei Yu Jing Li Tao Jiang Source Type: research

Identification of 2-hydroxybenzoic acid derivatives as selective SIRT5 inhibitors
In this study, we report the identification of the hit compound 11 bearing a 2-hydroxybenzoic acid functional group as a novel SIRT5-selective inhibitor via our medium-throughput thermal shift screening assay. Hit 11 stabilizes SIRT5 in a dose-dependent manner and shows moderate inhibitory activity against SIRT5 and high subtype selectivity over SIRT1, 2, and 3 in a trypsin coupled enzyme-based assay. The carboxylic acid and the adjacent hydroxyl group of 11 are essential for maintaining activity. To further improve the potency of compound 11, a lead optimization was carried out, resulting in compound 43 with a 10-fold imp...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Yanghan Liu Bikash Debnath Surinder Kumar David B Lombard Nouri Neamati Source Type: research

An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric cancer
Eur J Med Chem. 2022 Jul 19;241:114617. doi: 10.1016/j.ejmech.2022.114617. Online ahead of print.ABSTRACTGastric cancer is a worldwide health problem. Chemotherapy and radiotherapy are of great importance in the management of advanced gastric cancer. However, their therapeutic efficacy is limited by off-target side effects. Peptide-drug conjugates (PDCs) are a novel strategy for tumor-targeted drug delivery to overcome the existing drug resistance mechanisms and improve antitumor effects. Kita-Kyushu lung cancer antigen 1 (KK-LC-1) is exclusively expressed in several types of cancer including gastric cancer, representing a...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Xiaotong Chen Fangcen Liu Xiaoxiao Yu Lin Li Jiayao Yan Xinjie Chen Qin Liu Baorui Liu Source Type: research

Novel analgesic/anti-inflammatory agents: 1,5-Diarylpyrrole nitrooxyethyl sulfides and related compounds as Cyclooxygenase-2 inhibitors containing a nitric oxide donor moiety endowed with vasorelaxant properties
Eur J Med Chem. 2022 Jul 22;241:114615. doi: 10.1016/j.ejmech.2022.114615. Online ahead of print.ABSTRACTThe design of compounds able to combine the selective inhibition of cyclooxygenase-2 (COX-2) with the release of nitric oxide (NO) is a promising strategy to achieve potent anti-inflammatory agents endowed with an overall safer profile and reduced toxicity upon gastrointestinal and cardiovascular systems. With the aim of generating novel and selective COX-2 inhibiting NO-donors (CINOD) and encouraged by the promising results obtained with our nitrooxy- and hydroxyethyl ethers 11 and 12 reported in previous works, we shi...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Mario Saletti Samuele Maramai Annalisa Reale Marco Paolino Simone Brogi Angela Di Capua Andrea Cappelli Gianluca Giorgi Danilo D'Avino Antonietta Rossi Carla Ghelardini Lorenzo Di Cesare Mannelli Roccaldo Sardella Andrea Carotti Gerald Woelkart Burkhard K Source Type: research

β-Nitrostyrene derivatives as broad range potential antifungal agents targeting fungal cell wall
Eur J Med Chem. 2022 Jul 16;240:114609. doi: 10.1016/j.ejmech.2022.114609. Online ahead of print.ABSTRACTThe prevalence of multidrug resistance has been increasingly witnessed during the past few decades. Resistance of human pathogenic fungi against the currently available antifungal agents has increased the frequency of fungal infections and associated mortality rates. The discovery of novel lead antifungal agents is important to challenge multidrug resistance. The present study examined the antifungal potential of chemically synthesized β-Nitrostyrene derivatives. Among the eight β-Nitrostyrene derivatives used in this...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Asiya Ramzan Sajad Ahmad Padder Khalid Z Masoodi Syed Shafi Inayatullah Tahir Reiaz Ul Rehman Rajendra Prasad Abdul Haseeb Shah Source Type: research

Design, synthesis, and biological evaluation of novel 7-substituted 10,11-methylenedioxy-camptothecin derivatives against drug-resistant small-cell lung cancer in vitro and in vivo
Eur J Med Chem. 2022 Jul 20;241:114610. doi: 10.1016/j.ejmech.2022.114610. Online ahead of print.ABSTRACTA series of novel 7-substituted 10,11-methylenedioxy-camptothecin (FL118) derivatives were designed, synthesized, and biologically evaluated. All the FL118 analogues showed significant cytotoxic activities in vitro with IC50 values in the nanomolar range and were more potent than topotecan. The most active compound 9c exhibited more significant anti-tumor activity against small-cell lung cancer (NCI-H446, H69, drug-resistant H69AR cells, drug-resistant NCI-H446/Irinotecan cells and drug-resistant NCI-H446/EP cells) in v...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Guorui Zhang Ruijuan Yin Xiufei Dai Guanzhao Wu Xin Qi Rilei Yu Jing Li Tao Jiang Source Type: research

Identification of 2-hydroxybenzoic acid derivatives as selective SIRT5 inhibitors
In this study, we report the identification of the hit compound 11 bearing a 2-hydroxybenzoic acid functional group as a novel SIRT5-selective inhibitor via our medium-throughput thermal shift screening assay. Hit 11 stabilizes SIRT5 in a dose-dependent manner and shows moderate inhibitory activity against SIRT5 and high subtype selectivity over SIRT1, 2, and 3 in a trypsin coupled enzyme-based assay. The carboxylic acid and the adjacent hydroxyl group of 11 are essential for maintaining activity. To further improve the potency of compound 11, a lead optimization was carried out, resulting in compound 43 with a 10-fold imp...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Yanghan Liu Bikash Debnath Surinder Kumar David B Lombard Nouri Neamati Source Type: research