Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

Molecules, Год журнала: 2022, Номер 27(14), С. 4606 - 4606

Опубликована: Июль 19, 2022

A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact catalytic pocket. The ability of congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, bind enzyme demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established excellent binding 10 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed proper a total exact energy -38.36 Kcal/Mol. also revealed crucial amino acids in through free decomposition and declared interactions variation inside via Protein-Ligand Interaction Profiler (PLIP). Being new, its structure optimized DFT. DFT mode VEGFR-2. ADMET (in silico) profiling indicated examined compound's acceptable range drug-likeness. synthesized condensation N-(4-(hydrazinecarbonyl)phenyl)benzamide N-(4-acetylphenyl)nicotinamide, where carbonyl group has been replaced imine group. in-vitro were consonant obtained silico results prohibited IC50 value 51 nM. Compound showed effects against MCF-7 HCT 116 cancer cell lines values 8.25 6.48 μM, revealing magnificent selectivity indexes 12.89 16.41, respectively.

Язык: Английский

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The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

Processes, Год журнала: 2022, Номер 10(7), С. 1391 - 1391

Опубликована: Июль 17, 2022

Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential designed compound revealed via molecular docking study that showed appropriate binding. Then, MD simulation (six studies) over period 100 ns performed confirm precise binding and optimum energy. Additionally, MM-GBSA reaffirmed perfect binding, exhibiting total energy −40.38 Kcal/Mol. experiments named essential amino acids in protein–ligand interaction, employing decomposition revealing diversity interactions 7 inside VEGFR-2 enzyme. As is new, DFT were utilized for structure optimization. results validated coherent interaction with A good value drug-likeness acknowledged silico ADMET studies. Interestingly, experimental vitro prohibitory better than sorafenib, demonstrating an IC50 25 nM. Notably, strong effects 10 against two cancer cell lines (MCF-7 HCT 116) established values 12.93 11.52 μM, disclosing high selectivity indexes 6.7 7.5, respectively.

Язык: Английский

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Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

Molecules, Год журнала: 2022, Номер 27(15), С. 5047 - 5047

Опубликована: Авг. 8, 2022

This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative previous concerned with development VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast (MCF-7), colorectal carcinoma (HCT116), hepatocellular (HepG2). The also kinase activity. biological testing fallouts showed that compound

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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Discovery of new quinoline and isatine derivatives as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative, docking and MD simulation studies

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер 41(21), С. 11535 - 11550

Опубликована: Янв. 8, 2023

A new set of quinoline and isatine derivatives were synthesized as antiangiogenic VEGFR-2 inhibitors. On a biological level, the in vitro ability obtained candidates to inhibit was found be strong with IC50 values range 76.64-175.50 nM. To investigate cytotoxicity safety, all compounds tested against panel four cancer cell lines (A549, Caco2, HepG2 MDA) well two normal (Vero WI-38). Interestingly, compound 12 exhibited noticeable A549, Caco2 MDA 5.40, 0.58 0.94 µM, respectively. These results better comparable that doxorubicin (0.70, 0.82 0.90 respectively) more than three folds higher selectivity index lines. Compound 9 prevented healing cells at low concentration. Also, compound's potential induce programmed death Caco-2 proved through significant down regulating expression Bcl2, Bcl-xl Survivin addition slight upregulation TGF-β gene. The cycle analysis indicated arrested G2/M phase. molecular docking studies revealed correct binding targeted similar sorafenib. Furthermore, MD experiments validated over 100 ns, MM-PBSA confirmed precise optimum energy. Finally, ADMET showed general drug-likeness safety compounds.Communicated by Ramaswamy H. Sarma.

Язык: Английский

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New theobromine derivative as apoptotic anti-triple-negative breast cancer targeting EGFR protein: CADD story

Journal of Molecular Structure, Год журнала: 2023, Номер 1294, С. 136336 - 136336

Опубликована: Авг. 8, 2023

Язык: Английский

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Computer-aided drug discovery of natural antiviral metabolites as potential SARS-CoV-2 helicase inhibitors

Journal of Chemical Research, Год журнала: 2024, Номер 48(1)

Опубликована: Янв. 1, 2024

In our quest to discover effective inhibitors against severe acute respiratory syndrome coronavirus 2 helicase, a diverse set of more than 300 naturally occurring antiviral metabolites was investigated. Employing advanced computational techniques, we initiated the selection process by analyzing and comparing co-crystallized ligand (VXG) helicase protein (PDB ID: 5RMM) identify compounds with structurally similar features potential for comparable binding. Through structural similarity pharmacophore research, 13 that shared important characteristics VXG were pinpointed. Subsequently, these candidates subjected molecular docking seven demonstrated favorable energy profiles accurate binding helicase. Among these, mycophenolic acid emerged as most promising candidate. To ensure safety viability selected compounds, conducted ADMET tests, which confirmed acid, atropine plumbagin. Building on results, performed additional analyses including various dynamics simulations. These investigations exhibited optimal maintaining flawless throughout Furthermore, Molecular Mechanics Poisson–Boltzmann Surface Area tests provided strong evidence successfully formed stable connection calculated free value −294 kJ mol −1 . encouraging findings provide solid foundation further in vitro vivo studies, three identified compounds. The efficacy treatment options coronavirus-19 warrants exploration may hold significant promise ongoing fight pandemic.

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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New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies

Molecules, Год журнала: 2022, Номер 27(18), С. 5859 - 5859

Опубликована: Сен. 9, 2022

Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with catalytic pocket EGFR. Molecular docking against wild (EGFRWT; PDB: 4HJO) and mutant (EGFRT790M; 3W2O) types EGFR-TK indicated that theobromine derivative had potential bind as an antiangiogenic inhibitor. The MD MM-GBSA experiments identified exact binding optimum energy dynamics. Additionally, DFT calculations studied electrostatic potential, stability, total electron density derivative. Both in silico ADMET toxicity analyses demonstrated its general likeness safety. We synthesized (compound XI) which showed IC50 value 17.23 nM for inhibition besides values 21.99 22.02 µM cytotoxicity A549 HCT-116 cell lines, respectively. Interestingly, XI expressed weak cytotoxic healthy W138 line (IC50 = 49.44 µM, 1.6 times safer than erlotinib), exhibiting high selectivity index 2.2. Compound arrested growth at G2/M stage increased incidence apoptosis.

Язык: Английский

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Novel promising benzoxazole/benzothiazole‐derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis

Archiv der Pharmazie, Год журнала: 2023, Номер 356(9)

Опубликована: Июнь 28, 2023

Eleven novel benzoxazole/benzothiazole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The compounds evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3, MCF-7 cells. Generally, the open with semicarbazide thiosemicarbazide moieties (10, 13a-c, 14, 17a,b) exhibited higher than derivatives closed glutarimide moiety (8a-d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, 4.71 µM MCF-7, respectively) 14 7.93, 8.23, 12.37, 5.43 µM, highest anticancer four tested cell lines. most active further in vitro on tumor necrosis factor-alpha (TNF-α), caspase-8 (CASP8), vascular endothelial growth factor (VEGF), nuclear kappa-B p65 (NF-κB p65) HCT-116 Compounds showed a remarkable significant reduction TNF-α. Furthermore, they elevation CASP8 levels. Also, significantly inhibited VEGF. addition, decreases level of NF-κB while demonstrated an insignificant decrease respect thalidomide. Moreover, our good silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.

Язык: Английский

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