Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1903 - 1917

Published: July 8, 2022

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids potential activity against VEGFR-2. The cytotoxic effects of synthesised derivatives Caco-2, HepG-2, MDA-MB-231 cell lines were investigated. Compound 12a found be most potent candidate investigated IC50 values 2, 10, 40 µM, respectively. Furthermore, tested in vitro for their VEGFR-2 inhibitory showing strong inhibition. Moreover, an viability study Vero non-cancerous line results reflected a high safety profile all compounds. further its apoptotic behaviour by assessing gene expression four genes (Bcl2, Bcl-xl, TGF, Survivin). Molecular dynamic simulations authenticated affinity, accurate binding, perfect dynamics compound

Language: Английский

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Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(13), P. 6912 - 6912

Published: June 21, 2022

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (Mpro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, molecular structure similarity study done with PRD_002214, co-crystallized ligand Mpro (PDB ID: 6LU7), favored thirty Subsequently, fingerprint respect to PRD_002214 resulted election sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, 278). Then, results docking versus PDB 6LU7 eight (128, 278) based on their binding affinities. toxicity studies for revealed that all them have good profiles. Finally, dynamic (MD) simulation experiments carried out 278, which exhibited best modes Mpro. MD tests luteoside (130) has greatest potential inhibit protease.

Language: 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, Journal Year: 2022, Volume and Issue: 10(7), P. 1391 - 1391

Published: July 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.

Language: Английский

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

Molecules, Journal Year: 2022, Volume and Issue: 27(15), P. 5047 - 5047

Published: Aug. 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

Language: Английский

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Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1884 - 1902

Published: July 8, 2022

A new series of 1H-pyrrole (6a-c, 8a-c), pyrrolo[3,2-d]pyrimidines (9a-c) and pyrrolo[3,2-e][1, 4]diazepines (11a-c) were designed synthesised. These compounds to have the essential pharmacophoric features EGFR Inhibitors, they shown anticancer activities against HCT116, MCF-7 Hep3B cancer cells with IC50 values ranging from 0.009 2.195 µM. value doxorubicin is 0.008 µM, 9a 9c showed 0.011 µM respectively HCT-116 cells. Compound 8b exerted broad-spectrum activity all tested cell lines an less than 0.05 was evaluated a panel kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 GSK3 alpha kinases 10-23% compared imatinib (1-10%). It has also arrested cycle at S phase. Its antiproliferative further augmented by molecular docking into active sites CDK2 cyclin A1.

Language: Английский

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

PLoS ONE, Journal Year: 2022, Volume and Issue: 17(9), P. e0272362 - e0272362

Published: Sept. 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.

Language: Английский

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Computer-aided drug design in anti-cancer drug discovery: What have we learnt and what is the way forward?

Informatics in Medicine Unlocked, Journal Year: 2023, Volume and Issue: 41, P. 101332 - 101332

Published: Jan. 1, 2023

The escalating prevalence of cancer on a global scale, coupled with the inadequacies present-day therapies and emergence drug-resistant strains, has necessitated development additional anti-cancer drugs. traditional drug discovery process is long complex, high failure rate new drugs in clinical trials further highlights need for computational approaches discovery. Computer-aided design (CADD), including molecular docking, dynamics simulations, QSAR analysis, machine learning, are employed to forecast efficacy potential compounds pinpoint most auspicious subsequent testing advancement. This article provides an overview contemporary It range small molecules that have been identified as capable impeding growth migration through various mechanisms, cell cycle arrest/apoptosis, signal transduction inhibition, angiogenesis, epigenetics, hedgehog pathway. also examines constraints techniques presents remedies surmount these limitations identification efficacious anticancer compounds.

Language: 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, Journal Year: 2022, Volume and Issue: 27(22), P. 7719 - 7719

Published: Nov. 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.

Language: 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, Journal Year: 2023, Volume and Issue: 41(21), P. 11535 - 11550

Published: Jan. 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.

Language: Английский

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Quinoxaline derivatives: Recent discoveries and development strategies towards anticancer agents

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 271, P. 116360 - 116360

Published: April 7, 2024

Cancer is a leading cause of death and major health problem worldwide. While many effective anticancer agents are available, most drugs currently on the market not specific, raising issues like common side effects chemotherapy. However, recent research hold promises for development more efficient safer drugs. Quinoxaline its derivatives becoming recognized as novel class chemotherapeutic with activity against different tumors. The present review compiles discusses studies concerning therapeutic potential quinoxaline derivatives, covering articles published between January 2018 2023.

Language: Английский

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