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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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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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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Therapeutic Insights of Indole Scaffold‐Based Compounds as Protein Kinase Inhibitors

ChemistrySelect, Год журнала: 2025, Номер 10(5)

Опубликована: Янв. 29, 2025

Abstract Cancer is deemed to be one of the most severe diseases, which accountable for elevated mortality rate after cardiovascular diseases. Despite huge numbers drugs that were approved by USFDA combat prevalence cancer, resistance diverse cancer types current medications as well their high toxicity becomes an obstacle in therapy. Thus, developing new with improved selectivity and efficiency cure various disease still imperative goal. Kinases are phosphorylating enzymes catalyze transfer phosphate from ATP tyrosine, serine threonine residues proteins, leads activation varied signaling pathways regulate cellular functions such differentiation, proliferation, migration angiogenesis. Abnormal phosphorylation diseases overexpression kinases was frequently observed different cancerous tissues. suppression kinase activity has stood out a strategic pathway Otherwise, indole core displayed privileged scaffold promising anticancer properties multi‐kinase effect. This review presents indole‐based agents inhibitors recent decade. In addition, interactions derivatives within active pocket have been highlighted. article comprises research reports 2014 until present.

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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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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New Theobromine Derivatives Inhibiting VEGFR-2: Design, Synthesis, Antiproliferative, Docking and Molecular Dynamics Simulations

Future Medicinal Chemistry, Год журнала: 2023, Номер 15(14), С. 1233 - 1250

Опубликована: Июль 1, 2023

Background: VEGFR-2 is one of the most effective targets in cancer treatment. Aim: The design and semi-synthesis new theobromine derivatives as potential inhibitors. Methods: In vitro silico evaluation synthesized compounds. Results: Compound 5b demonstrated excellent antiproliferative inhibitory effects with significant apoptotic activity. It modulated immune response by increasing IL-2 reducing TNF-α levels. Docking molecular dynamics simulations revealed compound’s binding affinity VEGFR-2. Lastly, computational absorption, distribution, metabolism, excretion toxicity studies indicated high compound for drug development. Conclusion: could be a promising anticancer agent targeting

Язык: Английский

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Recent drug design strategies and identification of key heterocyclic scaffolds for promising anticancer targets

Pharmacology & Therapeutics, Год журнала: 2023, Номер 254, С. 108579 - 108579

Опубликована: Дек. 30, 2023

Язык: Английский

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Exploring binding potential of two new indole alkaloids from Nauclea officinalis against third and fourth generation EGFR: druglikeness, in silico ADMET, docking, DFT, molecular dynamics simulation, and MMGBSA study

Natural Product Research, Год журнала: 2024, Номер unknown, С. 1 - 8

Опубликована: Янв. 11, 2024

This study investigates the anti-cancer potential of recently discovered indole alkaloids from Nauclea Officinalis against third and fourth-generation EGFR mutations using computational tools. Through ADMET profiling, druglikeness prediction, docking, simulations, we assessed their pharmacokinetics, binding interactions, stability. Promising affinity were observed, particularly for (±)-19-O-butylangustoline, which demonstrated stronger both mutants. MD simulations confirmed stable with (±)-19-O-butylangustoline exhibiting highest These findings highlight these as agents, warranting further optimisation therapeutic development. informs through insights into molecular properties energetics.

Язык: Английский

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