scholarly journals Synthesis, Biological Activities and Docking Studies of Novel 4-(Arylaminomethyl)benzamide Derivatives as Potential Tyrosine Kinase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3543
Author(s):  
Elena Kalinichenko ◽  
Aliaksandr Faryna ◽  
Viktoria Kondrateva ◽  
Alena Vlasova ◽  
Valentina Shevchenko ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Biological Activities ◽  
Data Bank ◽  
Docking Studies ◽  
Cytotoxicity Activity ◽  
Her 2 ◽  
Solid Cell ◽  
New Compounds

A number of new compounds containing the 4-(aminomethyl)benzamide fragment as a linker were designed and synthesized, and their biological activities were evaluated as potential anticancer agents. The cytotoxicity activity of the designed compounds was studied in two hematological and five solid cell lines in comparison with the reference drugs. Targeted structures against eight receptor tyrosine kinases including EGFR, HER-2, HER-4, IGF1R, InsR, KDR, PDGFRa, and PDGFRb were investigated. The majority of the compounds showed a potent inhibitory activity against the tested kinases. The analogues 11 and 13 with the (trifluoromethyl)benzene ring in the amide or amine moiety of the molecule were proven to be highly potent against EGFR, with 91% and 92% inhibition at 10 nM, respectively. The docking of synthesized target compounds for nine protein kinases contained in the Protein Data Bank (PDB) database was carried out. The molecular modeling results for analogue 10 showed that the use of the 4-(aminomethyl)benzamide as a flexible linker leads to a favorable overall geometry of the molecule, which allows one to bypass the bulk isoleucine residue and provides the necessary binding to the active center of the T315I-mutant Abl (PDB: 3QRJ).

scholarly journals Docking studies, synthesis, characterization, and cytotoxicity activity of new bis-chalcones derivatives

2021 ◽  
Vol 8 (4) ◽  
pp. 4294-4305
Author(s):  
Mohammad Murwih Alidmat ◽  
Melati Khairuddean ◽  
Salizawati Muhamad Salhimi ◽  
Mohammad Al-Amin
Keyword(s):  
Inhibitory Concentration ◽  
Data Bank ◽  
2D Nmr ◽  
Docking Studies ◽  
Standard Drug ◽  
Discovery Studio ◽  
Cytotoxicity Activity ◽  
Diphenyl Tetrazolium Bromide ◽  
New Compounds ◽  
Mcf 7

Introduction: A bis-chalcones were prepared by the reaction of terephthalaldehyde with 3-acetyl-2,5-dichlorothiophene or 3-acetyl- 5-chlorothiophene and reaction cyclo ketone derivatives with phenyl aldehyde derivatives in good yields. Methods: The molecular docking studies were conducted using the Discovery Studio (DSv4.5) and MG. Tools installed in Window 10. The cancer receptor (3ERT) was downloaded from the protein data bank (PDB). All new compounds were characterized by IR, 1H-NMR, 13C-NMR, 2D-NMR, and CHN elemental analysis. The anticancer activity of the synthesized compounds was determined using MTT (3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) reduction assay against MCF-7 cells, and then the minimum inhibitory concentration (IC50) was determined with the reference of the standard drug tamoxifen. Results: The results showed that compound 6 showed more potent activity in inhibiting growth on both types of MCF-7 compared to reference tamoxifen.    

scholarly journals Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 92 ◽  
Author(s):  
Alessia Catalano ◽  
Domenico Iacopetta ◽  
Michele Pellegrino ◽  
Stefano Aquaro ◽  
Carlo Franchini ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Viral Infections ◽  
Drug Repositioning ◽  
Biological Activities ◽  
Antiviral Treatment ◽  
Far East ◽  
Mild Disease ◽  
To Come ◽  
The Uk

Antimicrobials have allowed medical advancements over several decades. However, the continuous emergence of antimicrobial resistance restricts efficacy in treating infectious diseases. In this context, the drug repositioning of already known biological active compounds to antimicrobials could represent a useful strategy. In 2002 and 2003, the SARS-CoV pandemic immobilized the Far East regions. However, the drug discovery attempts to study the virus have stopped after the crisis declined. Today’s COVID-19 pandemic could probably have been avoided if those efforts against SARS-CoV had continued. Recently, a new coronavirus variant was identified in the UK. Because of this, the search for safe and potent antimicrobials and antivirals is urgent. Apart from antiviral treatment for severe cases of COVID-19, many patients with mild disease without pneumonia or moderate disease with pneumonia have received different classes of antibiotics. Diarylureas are tyrosine kinase inhibitors well known in the art as anticancer agents, which might be useful tools for a reposition as antimicrobials. The first to come onto the market as anticancer was sorafenib, followed by some other active molecules. For this interesting class of organic compounds antimicrobial, antiviral, antithrombotic, antimalarial, and anti-inflammatory properties have been reported in the literature. These numerous properties make these compounds interesting for a new possible pandemic considering that, as well as for other viral infections also for CoVID-19, a multitarget therapeutic strategy could be favorable. This review is meant to be an overview on diarylureas, focusing on their biological activities, not dwelling on the already known antitumor activity. Quite a lot of papers present in the literature underline and highlight the importance of these molecules as versatile scaffolds for the development of new and promising antimicrobials and multitarget agents against new pandemic events.

scholarly journals Synthesis of Novel 1,2,4-Triazolyl Coumarin Derivatives as Potential Anticancer Agents

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Lamya H. Al-Wahaibi ◽  
Hanaa M. Abu-Melha ◽  
Diaa A. Ibrahim
Keyword(s):  
Colon Cancer ◽  
Molecular Docking ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Hct116 Cell ◽  
Human Colon ◽  
Docking Studies ◽  
Coumarin Derivatives ◽  
Human Colon Cancer

A series of novel coumarin derivatives carrying 1,2,4-triazole or 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole moieties were prepared and evaluated in vitro as anticancer in the human colon cancer (HCT116) cell line. The derivatives 4c and 8c exhibited marked anticancer activity with IC50 values 4.363 and 2.656 µM, respectively. The molecular docking studies suggested possible interaction with tyrosine kinases (CDK2).

Design, Synthesis, Cytotoxic Activity and Apoptosis-inducing Action of Novel Cinnoline Derivatives as Anticancer Agents

2018 ◽  
Vol 18 (8) ◽  
pp. 1208-1217 ◽  
Author(s):  
Manal M. Kandeel ◽  
Aliaa M. Kamal ◽  
Bassem H. Naguib ◽  
Marwa S.A. Hassan
Keyword(s):  
Tyrosine Kinase ◽  
Cytotoxic Activity ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Topoisomerase I ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Normal Breast ◽  
Biologically Active

Aims: Tyrosine kinases and topoisomerase I are common target enzymes for the majority of the anticancer agents. In contrast to quinazolines and quinolines, kinase inhibitors and topoisomerase inhibitors incorporating cinnoline scaffold are relatively infrequent. Thus the aim of this work was to replace the former scaffolds with the latter one. Eighteen novel cinnoline derivatives were designed, synthesized and characterized using both microanalytical and spectral data. Methods: The cytotoxic activity of the new compounds was screened in vitro against both human breast cancer cells and normal breast cells. Results: The enzymatic inhibition activity of promising candidates against both epidermal growth factor receptor tyrosine kinase and topoisomerase I was accomplished. Conclusions: Cell cycle profiles were observed at IC50 doses of representative biologically active compounds. Compound 7 represented a new scaffold incorporating triazepinocinnoline ring system and showed outstanding cytotoxic activity against MCF-7 (0.049 µM), tyrosine kinase inhibition (0.22 µM), apoptosis percentage and the highest selectivity index.

Synthesis and Anticancer Activity of Benzimidazole/Benzoxazole Substituted Triazolotriazines in Hepatocellular Carcinoma

2020 ◽  
Vol 19 (17) ◽  
pp. 2120-2129 ◽  
Author(s):  
Sakineh Dadashpour ◽  
Tuba T. Küçükkılınç ◽  
Ayse Ercan ◽  
Seyed J. Hosseinimehr ◽  
Nima Naderi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Biological Evaluation ◽  
Kinase Assay ◽  
Drug Candidate ◽  
Surface Receptors ◽  
Anticancer Mechanism

Background: Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer. Objective: The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents. Methods: A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells. Results: Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition. Conclusion: Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.

The development of 3-substituted indolin-2-one derivatives as kinase inhibitors for cancer therapy

2021 ◽  
Vol 28 ◽  
Author(s):  
Changqing Xu ◽  
Yang Liu ◽  
Guisen Zhao
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Cancer Therapy ◽  
Tyrosine Kinases ◽  
Recent Progress ◽  
Kinase Inhibitors ◽  
Response Rate ◽  
Docking Studies ◽  
Structure Activity ◽  
Molecular Aspects

: Kinases are pivotal regulators in tumorigenesis and metastasis by modulating the expression of oncogenes and the transcription of antioncogenes directly or indirectly. Correspondingly, multifarious 3-substituted indolin-2-one derivatives as selective kinase inhibitors for cancer therapy exhibited a low nanomolar activity with prominent efficacy, superior response rate and admirable tolerability. Particularly, certain 3-substituted indolin-2-one derivatives have met the requirements for clinical trials or the pharmaceutical market. Herein, we focus on the traits of 3-substituted indolin-2-one derivatives as kinase inhibitors for cancer therapy, overview recent progress of 3-substituted indolin-2-one derivatives as kinase inhibitors for cancer therapy, analyze the selectivity for tyrosine kinases inhibitors and serine/threonine kinases inhibitors from the molecular aspects based on the molecular docking studies, summarize the structure-activity relationships (SARs) as selective kinase inhibitors and provide our perspectives for the development of 3-substituted indolin-2-one derivatives as kinase inhibitors for cancer therapy.

Synthesis, anticancer activity, SAR and binding mode of interaction studies of substituted pentanoic acids: part II

2021 ◽  
Author(s):  
Sanchita Datta ◽  
Amit Kumar Halder ◽  
Nilanjan Adhikari ◽  
Sk Abdul Amin ◽  
Sanjib Das ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Leukemia Cell ◽  
Binding Mode ◽  
Docking Studies ◽  
Leukemia Cell Line ◽  
Pentanoic Acid ◽  
Dna Deformation ◽  
Pharmacokinetic Properties ◽  
New Compounds ◽  
Inhibiting Property

Aim: Our previous results suggest that phenyl/naphthylacetyl pentanoic acid derivatives may exhibit dual MMP-2 and HDAC8 inhibitory activities and show effective cytotoxic properties. Methodology: Here, 13 new compounds (C1–C13) were synthesized and characterized. Along with these new compounds, 16 previously reported phenyl/napthylacetyl pentanoic acid derivatives (C14–C29) were biologically evaluated. Results: Compounds C6 and C27 showed good cytotoxicity against leukemia cell line Jurkat E6.1. The mechanisms of cytotoxicity of these compounds were confirmed by DNA deformation assay and reactive oxygen species assay. MMP-2 and HDAC8 expression assays suggested the dual inhibiting property of these two compounds. These findings were supported by results of molecular docking studies. In silico pharmacokinetic properties showed compounds C6 and C27 have high gastrointestinal absorption. Conclusion: This study highlights the action of phenyl/naphthylacetyl pentanoic acid derivatives as anticancer agents.

scholarly journals Design, Synthesis and In Vitro Biological Evaluation Of N-(2-Aminophenyl)-3-Quinolin-4-yl -Prop-2-enamide Derivatives As Novel Colon Anticancer Agents

2020 ◽  
Vol 13 (3) ◽  
pp. 132-139
Author(s):  
Sunita S. Gagare ◽  
Vishnu P. Choudhari ◽  
Ashish Jain
Keyword(s):  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Assay Method ◽  
Histone Acetyl Transferase ◽  
Histone Proteins ◽  
Histone Deacetylase Inhibition ◽  
Cytotoxicity Activity

Acetylation and deacetylation of histone proteins is regulated through two enzymes; acetylation is mediated through histone acetyl transferase (HAT) whereas deacetylation is mediated through histone deacetylase (HDAC). Histone deacetylase removes acetyl group of lysine residue on histone proteinthis makes negatively charged histone able to bind with DNA containing positive centers. In this way DNA remain in compact form with histone proteins. Therefore the transcription or replication enzymes and cofactors not able to bind such compact DNA structure. Histone deacetylase inhibition results into inhibition of various transcription activities which may get accelerated during cancer development. The aim of proposed study is to develop effective isoform selective Histone deacetylase inhibitor. Synthesis of N-(2-Aminophenyl)-3-Quinolin-4-yl-Prop-2-Enamide derivatives from isatin and its derivatives was achieved. Synthesis was carried out in two steps with good yield. 21 Compounds were synthesized and found to be effective with IC50s in between 3.694 - 38.4µmol in human HCT-116, COLO 205 and COLO 320 DM colon cancer cells in vitro. For the cytotoxicity activity study MTT assay method was adopted. Docking studies were performed initially with HDAC8 enzyme using V-life MDS software for synthesized compounds and had selected best fit molecules for synthesis. The synthesized molecules are effective as colon anticancer agents.

Cysteine-targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions

2019 ◽  
Vol 26 (31) ◽  
pp. 5811-5824 ◽  
Author(s):  
Chunqi Hu ◽  
Xiaowu Dong
Keyword(s):  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Clinical Success ◽  
Biological Activities ◽  
Binding Pocket ◽  
Specific Protein ◽  
Covalent Bonds ◽  
Irreversible Inhibitors ◽  
Covalent Inhibitors

Tyrosine kinases are a subgroup of a large class of protein kinases that transfer phosphate groups from ATP to various amino acid residues. By phosphorylating the tyrosine residues, the tyrosine kinases are responsible for the activation of various proteins through signal transduction cascades, which serves as a ubiquitous mechanism of cell signaling. The frequent success of many tyrosine kinase inhibitors (TKIs) in clinical success and diseasecausing mutations in protein kinases suggests that a large number of kinases may represent therapeutically relevant targets. To date, most of the clinical and preclinical TKIs are ATPcompetitive non-covalent inhibitors, which achieve their selectivity by recognizing the unique features of specific protein kinases. Of growing interest now in the scientific community is the development of irreversible inhibitors that form covalent bonds with cysteines or other nucleophilic residues in the ATP binding pocket. Irreversible TKIs have many potential advantages including prolonged pharmacodynamics, reasonable compound design suitability, high potency, and the ability to validate pharmacological specificity by mutations in reactive cysteine residues. Here, we review recent efforts to develop cysteine-targeting irreversible TKIs and to discuss their patterns of configuration that identify adenosine triphosphate binding pockets and their biological activities.

scholarly journals Design, synthesis, anticancer activity and docking studies of theophylline containing 1,2,3-triazoles with variant amide derivatives

MedChemComm ◽  
2017 ◽  
Vol 8 (1) ◽  
pp. 176-183 ◽  
Author(s):  
Radhakrishnam Raju Ruddarraju ◽  
Adharvana Chari Murugulla ◽  
Ravindar Kotla ◽  
Muni Chandra Babu Tirumalasetty ◽  
Rajendra Wudayagiri ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Biological Activities ◽  
Docking Studies ◽  
Design Synthesis ◽  
Amide Derivatives

A new series of theophylline analogues containing 1,2,3-triazoles with different amide groups (22–41) has been designed and synthesized, and their biological activities have been evaluated as potential anticancer agents.

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