scholarly journals Unexpected Synthesis, Single-Crystal X-ray Structure, Anticancer Activity, and Molecular Docking Studies of Certain 2–((Imidazole/Benzimidazol–2–yl)thio)–1–arylethanones

Crystals ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 446
Author(s):  
Tarfah Al-Warhi ◽  
Mohamed Said ◽  
Mahmoud El Hassab ◽  
Nada Aljaeed ◽  
Hazem Ghabour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Single Crystal ◽  
Cell Lines ◽  
Docking Study ◽  
Anticancer Activities ◽  
Molecular Docking Study ◽  
X Ray ◽  
Mcf 7

In connection with our research program concerning development of novel effective benzimidazole-based anticancer candidates, herein we describe a new unexpected synthetic route to obtain a series of 2–((imidazole/benzimidazol2–yl)thio)1–arylethanones endowed with promising anti-breast cancer and Cyclin-dependent kinase 2 (CDK2) inhibitory activities. Contrary to expectations, products for the reaction of 2–mercaptoimidazole/benzimidazole 2a,b with β–keto esters 6a–c were unambiguously assigned as 2–((imidazol/benzimidazol2–yl)thio)1–arylethanones 10a–f based on NMR spectroscopy and single-crystal X-ray crystallographic analyses. In vitro anticancer activities for herein reported imidazole/benzimidazoles 10a–f were assessed through a cell-based assay against human breast cancer T4–7D and MCF–7 cell lines. Benzimidazoles 10d–f exerted better anti-proliferative action towards T4–7D and MCF–7 cell lines than their corresponding imidazole counterparts 10a–c. Furthermore, a molecular docking study suggested CDK2 kinase as a potential enzymatic target for benzimidazoles 10d–f, and investigated their possible binding pattern and interactions within CDK2 active site. Thereafter, benzimidazoles 10d–f were in vitro examined for their CDK2 inhibitory action, where they exerted good activity. Finally, several key ADME and druglikeness properties were predicted by the SwissADME online tool. Interestingly, benzimidazoles 10d–f were found to have no violations in all druglikeness rules (Veber, Lipinski, Ghose, Muegge, and Egan). In addition, they had neither PAINS nor structural alerts (Brenks). In conclusion, benzimidazoles 10d–f demonstrated not only a promising anticancer activities but also an acceptable ADME and physicochemical properties especially benzimidazole 10e.

scholarly journals Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2518
Author(s):  
Sawsan Mahmoud ◽  
Doaa Samaha ◽  
Mosaad S. Mohamed ◽  
Nageh A. Abou Taleb ◽  
Mohamed A. Elsawy ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Tumor Cell ◽  
Cell Lines ◽  
Antitumor Agents ◽  
Binding Free Energy ◽  
Docking Study ◽  
Tumor Cell Lines ◽  
Molecular Docking Study ◽  
Mcf 7

Protein tyrosine kinases (PTKs) are the most potential therapeutic targets for cancer. Herein, we present a sound rationale for synthesis of a series of novel 2-(methylthio), 2-(substituted alkylamino), 2-(heterocyclic substituted), 2-amino, 2,4-dioxo and 2-deoxo-5-deazaalloxazine derivatives by applying structure-based drug design (SBDD) using AutoDock 4.2. Their antitumor activities against human CCRF-HSB-2, KB, MCF-7 and HeLa have been investigated in vitro. Many 5-deazaalloxazine analogs revealed high selective activities against MCF-7 tumor cell lines (IC50: 0.17–2.17 µM) over HeLa tumor cell lines (IC50 > 100 µM). Protein kinase profiling revealed that compound 3h induced multi- targets kinase inhibition including −43% against (FAK), −40% against (CDKI) and −36% against (SCR). Moreover, the Annexin-V/PI apoptotic assay elucidate that compound 3h showed 33% and potentially 140% increase in early and late apoptosis to MCF-7 cells respectively, compared to the control. The structure-activity relationship (SAR) and molecular docking study using PTK as a target enzyme for the synthesized 7-deazaalloaxazine derivatives were investigated as potential antitumor agents. The AutoDock binding affinities of the 5-deazaalloxazine analogs into c-kit PTK (PDB code: 1t46) revealed reasonable correlations between their AutoDock binding free energy and IC50.

Design, Synthesis, In Vitro Anti-cancer Activity, ADMET Profile and Molecular Docking of Novel Triazolo[3,4-a]phthalazine Derivatives Targeting VEGFR-2 Enzyme

2018 ◽  
Vol 18 (8) ◽  
pp. 1184-1196 ◽  
Author(s):  
Abdel-Ghany A. El-Helby ◽  
Helmy Sakr ◽  
Rezk R.A. Ayyad ◽  
Khaled El-Adl ◽  
Mamdouh M. Ali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Cell Lines ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Kinase Assay ◽  
Anticancer Activities ◽  
In Silico Admet ◽  
Human Colon Adenocarcinoma ◽  
Mcf 7

Background: Extensive studies were reported in the synthesis of several phthalazine derivatives as promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective of present research work is the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR-2 inhibitors (e.g vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR-2 inhibitors at four different positions. </P><P> Material and Methods: A correlation between structure and biological activity of our designed phthalazines was established using molecular docking and VEGFR-2 kinase assay. Results and Discussion: In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03 and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested compounds. Most of our designed compounds exhibited good ADMET profile. Conclusion: The obtained results showed that, the most active compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs.

scholarly journals Design, Synthesis, Molecular Docking, ADME and Biological Evaluation Studies of Some New 1,3,4-oxadiazole Linked Benzimidazoles as Anticancer Agents and Aromatase Inhibitors

2021 ◽  
Author(s):  
ulviye acar çevik ◽  
Ismail Celik ◽  
Ayşen IŞIK ◽  
Yusuf Özkay ◽  
Zafer Asım Kaplancıklı
Keyword(s):  
Molecular Docking ◽  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Evaluation Studies ◽  
Biological Evaluation ◽  
Binding Modes ◽  
Anticancer Activities ◽  
Mcf 7

Abstract In this study, due to the potential anticancer effects of the benzimidazole ring system, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by 1H NMR, 13C NMR, and MS spectra analyses. In the in vitro anticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5a exhibited the most potent activity with IC50 values of 5,165±0,211 μM and 5,995±0,264 μM against MCF-7 and HepG2 cell lines. Compound 5a was included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5c was also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 (mouse embryo fibroblast cell line) cell line. In vitro, enzymatic inhibition assays of aromatase enzyme were performed for compound 5a acting on the MCF-7 cell line. For compound 5a, in silico molecular docking against aromatase enzyme was performed to determine possible protein-ligand interactions and binding modes.

scholarly journals Design, Synthesis, and Molecular Docking Study of Novel Heterocycles Incorporating 1,3,4-Thiadiazole Moiety as Potential Antimicrobial and Anticancer Agents

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1066 ◽  
Author(s):  
Mohamed El-Naggar ◽  
Hanan A. Sallam ◽  
Safaa S. Shaban ◽  
Salwa S. Abdel-Wahab ◽  
Abd El-Galil E. Amr ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Human Cancer ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Reference Drug ◽  
Human Cancer Cell Lines ◽  
Dhfr Inhibitors

A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic and antifungal controls, respectively. Compounds 6, 14, and 15 exhibited antitumor activity against four human cancer cell lines, CCRF-CEM leukemia, HCT-15 colon, PC-3 prostate, and UACC-257 melanoma cell lines using Doxorubicin as a reference drug. Compounds 10, 13, 14, and 15 proved to be the most active DHFR inhibitors with an IC50 range of 0.04 ± 0.82–1.00 ± 0.85 µM, in comparison with Methotrexate (IC50 = 0.14 ± 1.38 µM). The highly potent DHFR inhibitors shared a similar molecular docking mode and made a critical hydrogen bond and arene‒arene interactions via Ser59 and Phe31 amino acid residues, respectively.

Virtual Combinatorial Library Design, Synthesis and In vitro Anticancer Assessment of -2-Amino-3-Cyanopyridine Derivatives

2018 ◽  
Vol 21 (2) ◽  
pp. 138-148 ◽  
Author(s):  
Sanal Dev ◽  
Sunil. R. Dhaneshwar ◽  
Bijo Mathew
Keyword(s):  
Virtual Screening ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Docking Study ◽  
Assay Method ◽  
Molecular Docking Study ◽  
Binding Interaction ◽  
Mcf 7

Aim and Objective: For the development of new class of anticancer agents, a series of novel 2-amino-3-cyanopyridine derivatives were designed from virtual screening with Glide program by setting Topoisomerase II as the target. Materials and Methods: The top ranked ten molecules from the virtual screening were synthesized by microwave assisted technique and investigated for their cytotoxic activity against MCF-7 and A- 549 cell lines by using sulforhodamine B assay method. Results: The most active compound 2-amino-4-(3,5-dibromo-4-hydroxyphenyl)-6-(2,4- dichlorophenyl) nicotinonitrile (CG-5) showed significant cytotoxic profile with (LC50 = 97.1, TGI = 29.9 and GI50 = <0.1 µM) in MCF-7 and (LC50= 93.0, TGI= 50.0 and GI50= <7 µM) in A-549 cell lines. A molecular docking study was performed to explore the binding interaction of CG-5with the active site of Topoisomerase II. Conclusion: It can be concluded that halogen substituent pyridine ring was benefit for cytotoxicity.

Novel Pyrazolyl Benzoxazole Conjugates: Design, Synthesis, Molecular Docking Studies and in vitro Anticancer Activities

2019 ◽  
Vol 16 (8) ◽  
pp. 619-626
Author(s):  
Arunkumar Thiriveedhi ◽  
Ratnakaram Venkata Nadh ◽  
Navuluri Srinivasu ◽  
Narayana Murthy Ganta
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Docking Studies ◽  
Anticancer Activities ◽  
Molecular Docking Studies ◽  
Hybrid Molecules ◽  
Mcf 7

Nowadays, hybrid drugs have gained a significant role in the treatment of different health problems. Most of the hybrid molecules with different heterocyclic moieties were proved to be potent anti-tumor agents in cancer chemotherapy. Hence, the present study is aimed at the evaluation of in vitro anticancer activity of novel hybrid molecules (pyrazolyl benzoxazole conjugates) and to investigate their anticancer activity by molecular docking studies. Designed, synthesized and characterized the novel pyrazolyl benzoxazole conjugates. Anticancer activity of these compounds was determined by SRB assay. Then molecular docking studies were carried out against proto-oncogene tyrosine-protein kinase (ATP-Src, PDB: 2BDF), a putative target for cancer. All the synthesized compound derivatives were evaluated against MCF-7, KB, Hop62 and A549 cancer cell lines. Compounds 9b and 9c exhibited excellent anticancer activities with GI50 values of <0.1 µM against MCF-7 and A549 cell lines. Compound 9e exhibited good antitumor activity on MCF-7 and A-549 with GI50 values of 0.12 µM and 0.19 µM respectively. Compound 9g showed better anticancer activity on A-549 cancer cell line with GI50 of 0.34 µM. The two-hybrid molecules 9b and 9c are found to be comparably potent with the standard drug doxorubicin and may act as drug lead compounds in medicinal chemistry aspect. The present docking investigation proved that having benzoxazole of compound 9c at the position of benzofuran of reference compound (N-acetyl pyrazoline derivative) might be valid for contributing to anti-cancer activity.

Synthesis, Characterization, Molecular Docking, In Vitro Biological Evaluation and In Vitro Cytotoxicity Study of Novel Thiazolidine-4-One Derivatives as Anti-Breast Cancer Agents‏‏

2021 ◽  
Vol 21 ◽  
Author(s):  
Zainab Y. Kadhim ◽  
Hasanain G.J. Alqaraghuli ◽  
Muna Tawfeeq Abd
Keyword(s):  
Breast Cancer ◽  
Antibacterial Activity ◽  
Molecular Docking ◽  
Cell Growth ◽  
Breast Cancer Cells ◽  
Docking Study ◽  
In Vitro Cytotoxicity ◽  
T1 And T2 ◽  
Mcf 7

Background: Thiazolidine-4-one is a promising class of heterocyclic compounds with interesting pharmacological and biological activities, such as anticancer and antibacterial. Therefore, many researchers have synthesized thiazolidine-4-ones and evaluated their biological potential for developing new drugs. Objective: In this study, two novel thiazolidine-4-one derivatives (T1 and T2) were synthesized and evaluated for their antibacterial activity toward Staphylococcus aureus, Escherichia coli and Proteus mirabilis. Also, the cytotoxic activities of compounds T1 and T2 were estimated against MCF-7 (HER2+, ER+ and ER+) and MDA-MB-231 (triple-negative) human breast cancer cell lines. The chemical structure of compounds T1 and T2 was proven using spectral techniques (FT-IR, 1HNMR, and 13C-NMR) and CHN elemental analysis. Methods: The synthesis of thiazolidine-4-one compounds was performed in two steps. The first step consisted of the formation of Schiff bases S1 and S2. In the second step, the synthesized Schiff bases were reacted with thioglycolic acid to prepared thiazolidine-4-one compounds T1 and T2. Hemolysis assay, molecular docking, cytotoxicity activity (MTT assay) and antibacterial activity (disc diffusion assay) were studied. Results: The hemolysis study demonstrated that the hemolytic ratio of compounds T1 and T2 at (1, 2 and 3) mg/ml was less than 4%. MTT assay showed that 100 µg/ml of compounds T1 and T2 diminish the MCF-7 cell growth up to 80.05 ± 1.72 and 69.85 ± 3.26 respectively after 72 hrs, while the same concentration of compounds T1 and T2 reduces the MDA-MB-231 cell growth up 70.28 ± 2.31 and 57.15 ± 1.49, respectively. The inhibition zone of compounds T1 and T2 were 12 mm at 50 mg/ml and 10 mm at 5 mg/ml in E. coli bacteria. Furthermore, a docking study was carried out to investigate the affinity and binding mode of compounds T1 and T2 towards the ERα, VEGF, and HER2 protein receptors in breast cancer cells. Data obtained from the docking study were exactly identical to that obtained from in vitro cytotoxicity assay. Conclusion: The results proved that compound T1 is an optimal anticancer agent toward breast cancer cells and the hemolysis study indicates the use of safety inside the body for compound T1. Synthesized compound T1 was most effective against MCF-7 cells compared to MDA-MB-231 cells and more effective than the reference drug tamoxifen in breast cell lines. The high cytotoxicity of compound T1 on the growth of MCF‐7 cells because T1 binds with a high degree of affinity to the estrogen and HER2 receptors, which in turn inhibits cell proliferation and induces apoptosis.

scholarly journals Am Synthesis, Docking Study and In vitro Anticancer Evaluation of Some New Flurbiprofen Derivatives Against MCF-7 and WRL-68 Cell Lines

2021 ◽  
Author(s):  
Kasim S. Hmood ◽  
Ammar A. Razzak Mahmood Kubba ◽  
Redha I Al-bayati ◽  
Abdulrahman M. Saleh
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Docking Study ◽  
Spectroscopic Techniques ◽  
Cytotoxic Assay ◽  
Molecular Docking Study ◽  
Thiourea Derivatives ◽  
Starting Point ◽  
Mcf 7

A new series of flurbiprofen derivatives containing thiosemicarbazide moiety (3-7)  was  synthesized from flurbiprofen as parent nucleus by  esterification, hydrazide formation, and  heating with different  aryl isothiocyanate substituents, respectively. Flurbiprofen was also treated with thiosemicarbazide in the  presence POCl3 as  a catalyst,   to produce 1,3,4 -thiadiazole -2-amine (8). Treatment of (8) with different aryl isothiocyanates  produced thiourea derivatives (9-12).  Also, the reaction of  (8)  with different benzoyl chloride substituents produced benzamide compounds (13-15). Eventually , treatment of (8)  with  ethyl acetoacetate(EAA) produced [1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one (16) .The new compounds were  characterized by spectroscopic techniques :FTIR,  1HNMR, and CHNS analysis. A molecular docking  study for  the  synthesized compounds (3-16), against the Vascular Endothelial Growth Factor receptor (VEGFR-2) was applied   and  it  indicated  that compounds 4,7,13, and 15,exhibited the optimum binding energy of     -6.77, -6.12,-6.68, and -6.43 kcal/mol, respectively. Target compounds were  also assessed  for their  in vitro anticancer effects  in a cell-line study. All  of the compounds tested  showed  the most plausible anticancer activity, compared to a positive control(Sorafenib), using in vitro  MTT cytotoxic assay ,against human breast tumor (MCF-7), and normal WRL-68 cell line. The in vitro results revealed that compounds 4,5,10,11,13, and 15 exhibited the highest inhibitory activity at their IC50 concentrations, against MCF-7 cell lines, as follows (122.7,113.9,95,7. 109.1,40.32 and 112.29µg/mL, respectively. While their cytotoxic effect against normal WRL-68 cell line at  their IC50 concentrations, as follow 210.2, 181.3 ,151.7,278.7,80.28, and 236 µg/mL, respectively, therefore,  such compounds were considered more selective toward MCF-7 than normal WRL-68,and their selectivity index (SI): 1.71,1.59,1.59 ,2.55 ,1.99 , and 2.10,respectively . Among the synthesized compounds, the compound 15 was chosen to screen its effect in vitro through multi-parameter cytotoxic assay against MCF-7 breast cancer implemented in High Content Screening (ArrayScan XTI, Thermo Scientific),which  could be taken in consideration as a starting point for the  development  of new anticancer drugs

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