Synthesis, Antiproliferative Activity, Apoptotic Profiling, and In‐silico ADME of New Thienylbenzamidine Derivatives

2021 ◽  
Vol 6 (30) ◽  
pp. 7644-7653
Author(s):  
Mohamed A. Ismail ◽  
Heba M. El‐Shafeai ◽  
Reem K. Arafa ◽  
Mohamed H. Abdel‐Rhman ◽  
Ehab Abdel‐Latif ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
In Silico

A New Series of Antileukemic Agents: Design, Synthesis, In Vitro and In Silico Evaluation of Thiazole-Based ABL1 Kinase Inhibitors

2020 ◽  
Vol 20 ◽  
Author(s):  
Ebru Zeytün ◽  
Mehlika D. Altıntop ◽  
Belgin Sever ◽  
Ahmet Özdemir ◽  
Doha E. Ellakwa ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
Cell Line ◽  
Antiproliferative Activity ◽  
In Silico ◽  
K562 Cell ◽  
Kinase Inhibitors ◽  
K562 Cell Line ◽  
Cytotoxic Effects ◽  
Atp Binding Site

Background: After the milestone approval of imatinib, more than 25 antitumor agents targeting kinases have been approved, and several promising candidates are in various stages of clinical evaluation. Objectives : Due to the importance of thiazole scaffold in targeted anticancer drug discovery, the goal of this work is the design of new thiazolyl hydrazones as potent ABL1 kinase inhibitors for the management of chronic myeloid leukemia (CML). Methods: New thiazolyl hydrazones (2a-p) were synthesized and investigated for their cytotoxic effects on K562 CML cell line. Compounds 2h, 2j and 2l showed potent anticancer activity against K562 cell line. The cytotoxic effects of these compounds on other leukemia (HL-60, MT-2 and Jurkat) and HeLa human cervical carcinoma cell lines were also investigated. Furthermore, their cytotoxic effects on mitogen-activated peripheral blood mononuclear cells (MA-PBMCs) were evaluated to determine their selectivity. Due to its selective and potent anticancer activity, compound 2j was benchmarked for its apoptosis-inducing potential on K562 cell line and inhibitory effects on eight different tyrosine kinases (TKs) including ABL1 kinase. In order to investigate the binding mode of compound 2j into the ATP binding site of ABL1 kinase (PDB: 1IEP), molecular docking study was conducted using MOE 2018.01 program. The QikProp module of Schrödinger’s Molecular modelling package was used to predict the pharmacokinetic properties of compounds 2a-p. Results: 4-(4-(Methylsulfonyl)phenyl)-2-[2-((1,3-benzodioxol-4-yl)methylene)hydrazinyl]thiazole (2j) showed antiproliferative activity against K562 cell line with an IC50 value of 8.87±1.93 µM similar to imatinib (IC50= 6.84±1.11 µM). Compound 2j was found to be more effective than imatinib on HL-60, Jurkat and MT-2 cells. Compound 2j also showed cytotoxic activity against HeLa cell line similar to imatinib. The higher selectivity index value of compound 2j than imatinib indicated that its antiproliferative activity was selective. Compound 2j also induced apoptosis in K562 cell line more than imatinib. Among eight TKs, compound 2j showed the strongest inhibitory activity against ABL1 kinase enzyme (IC50= 5.37±1.17 µM). According to molecular docking studies, compound 2j exhibited high affinity to the ATP binding site of ABL1 kinase forming significant intermolecular interactions. On the basis of in silico studies, this compound did not violate Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 2j stands out as a potential orally bioavailable ABL1 kinase inhibitor for the treatment of CML.

scholarly journals Potential Anticancer Lipoxygenase Inhibitors from the Red Sea-Derived Brown Algae Sargassum cinereum: An In-Silico-Supported In-Vitro Study

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 416
Author(s):  
Sami I. Alzarea ◽  
Abeer H. Elmaidomy ◽  
Hani Saber ◽  
Arafa Musa ◽  
Mohammad M. Al-Sanea ◽  
...  
Keyword(s):  
Red Sea ◽  
Antiproliferative Activity ◽  
Inhibitory Activity ◽  
Brown Algae ◽  
In Silico ◽  
Active Sites ◽  
In Vitro Study ◽  
Lipoxygenase Inhibitors ◽  
Phytochemical Investigation

LC-MS-assisted metabolomic profiling of the Red Sea-derived brown algae Sargassum cinereum “Sargassaceae” dereplicated eleven compounds 1–11. Further phytochemical investigation afforded two new aryl cresol 12–13, along with eight known compounds 14–21. Both new metabolites, along with 19, showed moderate in vitro antiproliferative activity against HepG2, MCF-7, and Caco-2. Pharmacophore-based virtual screening suggested both 5-LOX and 15-LOX as the most probable target linked to their observed antiproliferative activity. The in vitro enzyme assays revealed 12 and 13 were able to inhibit 5-LOX more preferentially than 15-LOX, while 19 showed a convergent inhibitory activity toward both enzymes. Further in-depth in silico investigation revealed the molecular interactions inside both enzymes’ active sites and explained the varying inhibitory activity for 12 and 13 toward 5-LOX and 15-LOX.

Novel N-bridged pyrazole-1-carbothioamides with potential antiproliferative activity: design, synthesis, in vitro and in silico studies

2021 ◽  
Vol 13 (20) ◽  
pp. 1743-1766
Author(s):  
Islam H El Azab ◽  
Essa M Saied ◽  
Alaa A Osman ◽  
Amir E Mehana ◽  
Hosam A Saad ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
In Silico ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Molecular Docking Study ◽  
In Silico Studies

Thiazole-substituted pyrazole is an important structural feature of many bioactive compounds, including antiviral, antitubercular, analgesic and anticancer agents. Herein we describe an efficient and facile approach for the synthesis of two series of 36 novel N-bridged pyrazole-1-phenylthiazoles. The antiproliferative activity of a set of representative compounds was evaluated in vitro against different human cancer cell lines. Among the identified compounds, compound 18 showed potent anticancer activity against the examined cancer cell lines. The in silico molecular docking study revealed that compound 18 possesses high binding affinity toward both SK1 and CDK2. Overall, these results indicate that compound 18 is a promising lead anticancer compound which may be exploited for development of antiproliferative drugs.

Synthesis, characterization, in silico approach and in vitro antiproliferative activity of RPF151, a benzodioxole sulfonamide analogue designed from capsaicin scaffold

2015 ◽  
Vol 1088 ◽  
pp. 138-146 ◽  
Author(s):  
Maurício T. Tavares ◽  
Kerly F.M. Pasqualoto ◽  
Jacco van de Streek ◽  
Adilson K. Ferreira ◽  
Ricardo A. Azevedo ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
In Silico

scholarly journals Lipophilic Salirasib analogs with enhanced antiproliferative activity against human solid tumor cell lines

2021 ◽  
Author(s):  
Exequiel O. J. Porta ◽  
María Sol Ballari ◽  
José M. Padrón ◽  
Guillermo R. Labadie
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Cancer Cell ◽  
Solid Tumor ◽  
Antiproliferative Activity ◽  
In Silico ◽  
Tumor Cell Lines ◽  
Human Solid Tumor ◽  
Physicochemical Features ◽  
Sar Analysis

Aim: We proposed to determine the antiproliferative activity of a series of synthetic salirasib analogs, presenting or not a 1,2,3-triazole linker, against five different cancer cell lines. Results: Bioassay, cheminformatic, and in silico ADME-Tox allowed the identification of new potent analogs. SAR analysis allowed the identification of structural and physicochemical features that benefit the antiproliferative activity. Conclusion: Isoprenyl R chains with three or more isoprene units, or long aliphatic R chains are the preferred ones within the active compounds. Likewise, we have identified three compounds with better activity profiles than salirasib against all the cell lines tested.

Synthesis, In Vitro Antiproliferative Activity, and In Silico Studies of New Anilinoquinazoline Derivatives as Potential AntitumorAgents

2020 ◽  
Vol 90 (12) ◽  
pp. 2410-2418
Author(s):  
M. K. Abdulwahab ◽  
R. Dzulkeflee ◽  
T. K. Han ◽  
R. A. Ruslan ◽  
K. H. Leong ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
In Silico ◽  
In Silico Studies

scholarly journals In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 4002
Author(s):  
Faisal A. Almalki ◽  
Ashraf N. Abdalla ◽  
Ahmed M. Shawky ◽  
Mahmoud A. El Hassab ◽  
Ahmed M. Gouda
Keyword(s):  
Cell Cycle ◽  
Schiff Bases ◽  
Mechanism Of Action ◽  
Antiproliferative Activity ◽  
In Silico ◽  
Experimental Studies ◽  
Free Software ◽  
Potential Mechanism ◽  
Mcf7 Cells ◽  
Cox 2

In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC50 = 0.01–40.50 μM) and one normal MRC5 (IC50 = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC50 = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G2/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.

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