Design, synthesis, and docking of novel thiazolidine‐2,4‐dione multitarget scaffold as new approach for cancer treatment DOI

Noura S. Hanafy,

Nada A. A. M. Aziz,

Sanadelaslam S. A. El‐Hddad

et al.

Archiv der Pharmazie, Journal Year: 2023, Volume and Issue: 356(7)

Published: May 5, 2023

Abstract Novel thiazolidine‐2,4‐diones have been developed and estimated as conjoint inhibitors of EGFR T790M VEGFR‐2 against HCT‐116, MCF‐7, A549, HepG2 cells. Compounds 6a, 6b , 6c were known to be the dominant advantageous congeners HCT116 (IC 50 = 15.22, 8.65, 8.80 µM), A549 7.10, 6.55, 8.11 MCF‐7 14.56, 6.65, 7.09 µM) 11.90, 5.35, 5.60 mass cell lines, correspondingly. Although compounds disclosed poorer effects than sorafenib 4.00, 4.04, 5.58, 5.05 tested sets, demonstrated higher actions erlotinib 7.73, 5.49, 8.20, 13.91 HCT116, cells, yet lesser performance on The hugely effective derivatives 4e–i 6a–c inspected versus VERO normal strains. 6b, 6c, 6a 4i found most derivatives, which suppressed by IC 0.85, 0.90, 1.50, 1.80 µM, respectively. Moreover, 6i could interfere with performing strongest 0.30, 0.35, 0.50, 1.00 What is more, represented satisfactory in silico computed ADMET profile.

Language: Английский

Identification of Novel Cyanopyridones and Pyrido[2,3-d]Pyrimidines as Anticancer Agents with Dual VEGFR-2/HER-2 Inhibitory Action: Synthesis, Biological Evaluation and Molecular Docking Studies DOI Creative Commons

Tarfah Al‐Warhi,

Al-Aliaa M. Sallam, Loah R. Hemeda

et al.

Pharmaceuticals, Journal Year: 2022, Volume and Issue: 15(10), P. 1262 - 1262

Published: Oct. 13, 2022

In the current work, we designed and synthesized three families of non-fused fused compounds based on cyanopyridone: derivatives 6-amino-1,2-dihydropyridine-3,5-dicarbonitrile (5a-f) 3,4,7,8-tetrahydro pyrimidine-6-carbonitrile (6a-b 7a-e). The newly compounds' structure were determined using a variety techniques, including 1H NMR, 13C mass spectrum, infrared spectroscopy, elemental analysis. developed tested for ability to inhibit growth breast adenocarcinoma (MCF-7) hepatic (HepG2) cell lines MTT assay. Some more effective towards cancer than standard treatment taxol. best antiproliferative activities demonstrated by cyanopyridones 5a 5e against MCF-7 line (IC50 = 1.77 1.39 μM, respectively) 6b HepG2 2.68 2.71 respectively). We further explored 5e, two most potent line, their VEGFR-2 HER-2. Finally, docking molecular dynamics simulations performed as part modeling investigation elucidate binding modes compounds, allowing thorough comprehension activity 5e.

Language: Английский

Citations

63
The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches DOI Open Access
Eslam B. Elkaeed, Reda G. Yousef, Hazem Elkady

et al.

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

Citations

45
Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation DOI Creative Commons
Alaa Elwan, Abdallah E. Abdallah,

Hazem A. Mahdy

et al.

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

Citations

45
Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations DOI
Ahmed A. Al‐Karmalawy, Mohamed S. Nafie, Moataz A. Shaldam

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 777 - 792

Published: Dec. 16, 2022

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising inhibitors. Therefore, two novel series of pyridazine-linked cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized investigate the inhibitory activity candidates. Notably, 8e 9e exhibited best inhibition profiles. Moreover, showed strong antitumor effects against both MCF-7 A549 cell lines. The on cycle apoptosis measured. Besides, evaluated its in vivo using solid Ehrlich carcinoma. reduction tumor weight volume greater than doxorubicin. Also, molecular docking ADME studies performed. Finally, SAR study conducted gain further insights into different potentials upon variable structural modifications.

Language: Английский

Citations

43
Computer-aided drug design in anti-cancer drug discovery: What have we learnt and what is the way forward? DOI Creative Commons
Opeyemi Iwaloye,

Paul Olamide Ottu,

Femi Olawale

et al.

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

Citations

39
(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 DOI Creative Commons
Reda G. Yousef, Hazem Elkady, Eslam B. Elkaeed

et al.

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

Citations

38
Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors DOI Creative Commons
Moataz A. Shaldam, Hadia Almahli, Andrea Angeli

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: April 25, 2023

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives CA inhibitory towards physiologically relevant hCA isoforms I, II, tumour-linked IX isoform, addition, activity was evaluated. The failed to inhibit that could be attributable steric effect of neighbouring methoxy group, whereas they displayed effect. Following that, 11b 12b tested their influence cycle disturbance, apoptotic potential. Finally, detailed molecular modelling analyses, including docking dynamics, carried out assess binding mode stability isatins.

Language: Английский

Citations

33
Discovery of new quinoline and isatine derivatives as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative, docking and MD simulation studies DOI
Mohammed S. Taghour, Hazem Elkady, Wagdy M. Eldehna

et al.

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

Citations

32
New theobromine derivative as apoptotic anti-triple-negative breast cancer targeting EGFR protein: CADD story DOI
Ibrahim H. Eissa, Reda G. Yousef, Hazem Elkady

et al.

Journal of Molecular Structure, Journal Year: 2023, Volume and Issue: 1294, P. 136336 - 136336

Published: Aug. 8, 2023

Language: Английский

Citations

30
Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers DOI
Ibrahim H. Eissa, Reda G. Yousef, Hazem Elkady

et al.

Computational Biology and Chemistry, Journal Year: 2023, Volume and Issue: 107, P. 107953 - 107953

Published: Aug. 30, 2023

Language: Английский

Citations

25