Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2,4-diones targeting VEGFR-2 and apoptosis pathway

PLoS ONE, Год журнала: 2022, Номер 17(9), С. e0272362 - e0272362

Опубликована: Сен. 23, 2022

We report herein, the design and synthesis of thiazolidine-2,4-diones derivatives as new inhibitors for VEGFR-2. The designed members were assessed their in vitro anticancer activity against four cancer cell lines; A549, Caco-2, HepG-2 MDA-MB-231. Compound 14a showed most potent effects lines (IC50 = 1.5 31.5 μM, respectively). Next, VEGFR-2 inhibitory activity, safety profiles selectivity indices examined all synthesized normal Vero line. (the safest member Caco-2 line) was further investigated its ability to inhibit cells migration healing. Moreover, apoptotic induction compound line by assessing genes (Bcl2, Bcl-xl, TGF, Survivin). results revealed that can exert apoptosis through significant reduction Bcl2, Survivin, TGF gene expression levels. Finally, deep computational studies including molecular docking, ADMET, toxicity studies, MD simulation carried out. Also, DFT calculations performed discussed, confirmed reactivity is expected be used a potential lead development with increased potency.

Язык: Английский

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Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

Molecules, Год журнала: 2022, Номер 27(15), С. 4898 - 4898

Опубликована: Июль 31, 2022

Breast cancer is the most common in women, responsible for over half a million deaths 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying importance such compounds drug discovery. Among heterocycles, thiazole-based have demonstrated broad range pharmacological activities. In present study, novel set 1,3-thiazole derivatives was designed synthesized based on coupling acetophenone derivatives, phenacyl bromide substituted as key reaction step. The activity screened against proliferation two breast cell lines (MCF-7 MDA-MB-231). all exhibited considerable antiproliferative toward cells compared to staurosporine, with no significant cytotoxicity epithelial cells. compound 4 potent activity, an IC50 5.73 12.15 µM MCF-7 MDA-MB-231 cells, respectively, staurosporine (IC50 = 6.77 7.03 µM, respectively). Exploring mechanistic insights revealed that possesses inhibitory vascular endothelial growth factor receptor-2 (VEGFR-2) 0.093 µM) Sorafenib 0.059 µM). Further, showed ability induce programmed death by triggering apoptosis necrosis cycle arrest at G1 stage while decreasing cellular population G2/M phase. Finally, detailed silico molecular docking studies affirmed this class binding affinity VEGFR2 proteins. Overall, these results indicate could be promising lead developing anti-breast compounds.

Язык: Английский

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Caspase-3 Activators as Anticancer Agents

Current Protein and Peptide Science, Год журнала: 2023, Номер 24(10), С. 783 - 804

Опубликована: Фев. 27, 2023

The cancer is still a major cause of death worldwide. Among different targets to design anticancer agents, caspase-3 an important target as its cleavage and activation lead apoptosis finally, cell death. Apart from some naturally occurring molecules, many small molecules have been reported activators.In view the above, objective has review published work on activators their activity get novel for designing improved therapeutic.Literature search carried out using engines like google, Elsevier, Science direct, RSC, etc. publications inducing in cells.In this review, showing discussed under broad chemical classes so provide insight into structural features responsible leading activity. also encompasses established drugs, organometallics activity.A large number including drugs shown Many potent may be useful optimization well they which agents drug development.

Язык: Английский

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Design and synthesis of new 4-(2-nitrophenoxy)benzamide derivatives as potential antiviral agents: molecular modeling and in vitro antiviral screening

New Journal of Chemistry, Год журнала: 2021, Номер 45(36), С. 16557 - 16571

Опубликована: Янв. 1, 2021

Novel benzamide derivatives as anti adenovirus, HSV-1, coxsackievirus, and SARS-CoV-2: in vitro silico study.

Язык: Английский

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In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

Molecules, Год журнала: 2021, Номер 26(20), С. 6151 - 6151

Опубликована: Окт. 12, 2021

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The aimed pick the most relevant inhibitor SARS-CoV-2 nsp10. At first, a structural similarity study against co-crystallized ligand, S-Adenosyl Methionine (SAM), nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. analysis culled 30 candidates. Secondly, fingerprint SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. docking studies picked 284. While ADMET expected likeness five candidates be drugs, toxicity 48 182. Finally, density-functional theory (DFT) suggested vidarabine (182) SARS-Cov-2 nsp10 inhibitor.

Язык: Английский

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In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

Molecules, Год журнала: 2021, Номер 26(21), С. 6593 - 6593

Опубликована: Окт. 30, 2021

Papain-like protease is an essential enzyme in the proteolytic processing required for replication of SARS-CoV-2. Accordingly, such important target development anti-SARS-CoV-2 agents which may reduce mortality associated with outbreaks A set 69 semi-synthesized molecules that exhibited structural features SARS-CoV-2 papain-like inhibitors (PLPI) were docked against coronavirus (PLpro) (PDB ID: (4OW0). Docking studies showed derivatives 34 and 58 better than co-crystallized ligand while 17, 28, 31, 40, 41, 43, 47, 54, 65 good binding modes free energies. The pharmacokinetic profiling study was conducted according to four principles Lipinski rules excluded derivative 31. Furthermore, ADMET toxicity 34, 47 have potential be drugs been demonstrated as safe when assessed via seven models. Finally, comparing molecular orbital energies electrostatic maps a DFT indicated 28 most promising candidate interact receptor (PLpro).

Язык: Английский

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Discovery of new quinoxaline-based derivatives as anticancer agents and potent VEGFR-2 inhibitors: Design, synthesis, and in silico study

Journal of Molecular Structure, Год журнала: 2021, Номер 1253, С. 132220 - 132220

Опубликована: Дек. 18, 2021

Язык: Английский

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(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide: A Novel Pyridine Derivative for Inhibiting Vascular Endothelial Growth Factor Receptor-2: Synthesis, Computational, and Anticancer Studies

Molecules, Год журнала: 2022, Номер 27(22), С. 7719 - 7719

Опубликована: Ноя. 9, 2022

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide (compound 10) was designed as an antiangiogenic VEGFR-2 inhibitor with the essential pharmacophoric structural properties to interact catalytic pocket of VEGFR-2. The derivative synthesized, and its structure confirmed through Ms, elemental, 1H, 13C spectral data. potentiality pyridine bind inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme indicated by molecular docking assessments. In addition, six dynamic (MD) experiments proved correct binding over 100 ns. Additionally, mechanics energies, combined generalized born surface area (MM-GBSA) analysis, identified precise optimum energy. To explore stability reactivity derivative, density functional theory (DFT) calculations, including electrostatic potential maps total electron density, were carried out. absorption, distribution, metabolism, excretion, toxicity (ADMET) analysis demonstrated general likeness safety. compound synthesized evaluate effects against protein, cancer, normal cells. in vitro results concordant silico results, because new displayed inhibition IC50 value 65 nM potent cytotoxic hepatic (HepG2) breast (MCF-7) cancer cell lines values 21.00 26.10 μM, respectively; additionally, it exhibited high selectivity indices (W-38) 1.55 1.25, respectively. obtained present 10 a lead for further biological investigation chemical modifications.

Язык: Английский

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Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 2063 - 2077

Опубликована: Июль 25, 2022

In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds (12d, 12f, 12i, 12l, 13a) displayed high growth inhibitory activities against HepG2 MCF-7 cell lines further investigated for their activities. The most potent anti-proliferative member 12 l (IC50 = 10.50 μM 15.21 MCF-7, respectively) had the promising activity 97.38 nM). A biological evaluation revealed that compound 12l could arrest mainly at Pre-G1 G1 phases. Furthermore, induce apoptosis in cells by 35.13%. likely, exhibited significant elevation caspase-3 level (2.98-fold) BAX (3.40-fold), reduction Bcl-2 (2.12-fold). Finally, docking studies indicated interactions with key amino acids similar way to sorafenib.

Язык: Английский

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Multi-Phase In Silico Discovery of Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors among 3009 Clinical and FDA-Approved Related Drugs

Processes, Год журнала: 2022, Номер 10(3), С. 530 - 530

Опубликована: Март 7, 2022

Proceeding our prior studies of SARS-CoV-2, the inhibitory potential against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) has been investigated for a collection 3009 clinical and FDA-approved drugs. A multi-phase in silico approach employed this study. Initially, molecular fingerprint experiment Remdesivir (RTP), co-crystallized ligand examined protein, revealed most similar 150 compounds. Among them, 30 compounds were selected after structure similarity experiment. Subsequently, docked (PDB ID: 7BV2). Aloin 359, Baicalin 456, Cefadroxil 1273, Sophoricoside 1459, Hyperoside 2109, Vitexin 2286 exhibited precise binding modes, as well best energies. To confirm obtained results, MD simulations experiments have conducted natural flavonoid glycoside that docking scores, RdRp 7BV2) 100 ns. The achieved results authenticated correct showing low energy optimum dynamics. Our team presents these outcomes scientists all over world to advance vitro vivo examinations COVID-19 promising

Язык: Английский

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