Design, Molecular Modeling, MD Simulations, Essential Dynamics, ADMET, DFT, Synthesis, Anti-Proliferative, and Apoptotic Evaluations of a New Anti-VEGFR-2 Nicotinamide Analogue DOI
Ibrahim H. Eissa, Eslam B. Elkaeed, Hazem Elkady

et al.

Current Pharmaceutical Design, Journal Year: 2023, Volume and Issue: 29(36), P. 2902 - 2920

Published: Nov. 1, 2023

Objectives: This study aims to design and evaluate (in silico in vitro) a new nicotinamide derivative as an inhibitor of VEGFR-2, major mediator angiogenesis. Methods: The following studies were performed; DFT calculations, molecular modelling, MD simulations, MM-GBSA, PLIP, PCAT studies. compound's (ADMET) analysis was also conducted. Subsequently, the compound ((E)-N-(4-(1-(2-(4-(4-Chlorobenzamido)benzoyl)hydrazono)ethyl) phenyl)nicotinamide) successfully synthesized designated X. In vitro, VEGFR-2 inhibition cytotoxicity X against HCT-116 A549 cancer cell lines normal Vero Apoptosis induction migration assay after treatment with evaluated. Results: calculations assigned stability reactivity Molecular docking simulations indicated its excellent binding VEGFR-2. Furthermore, MM-GBSA analysis, PLIP experiments, confirmed X’s correct optimal dynamics energy. ADMET expressed general likeness safety. vitro assays demonstrated that effectively inhibited IC50 value 0.319 ± 0.013 μM displayed lines, values 57.93 78.82 μM, respectively. Importantly, exhibited minimal toxicity towards non-cancerous (IC50 = 164.12 μM). Additionally, significantly induced apoptosis their potential migrate heal. Conclusion: summary, presented has identified promising candidate for development novel apoptotic lead anticancer drug.

Language: Английский

Novel promising benzoxazole/benzothiazole‐derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis DOI
Hazem Elkady, Khaled El‐Adl,

Helmy Sakr

et al.

Archiv der Pharmazie, Journal Year: 2023, Volume and Issue: 356(9)

Published: June 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.

Language: Английский

Citations

20
Design, synthesis, in silico studies, and biological evaluation of novel pyrimidine-5-carbonitrile derivatives as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers DOI Creative Commons
Abdulrahman M. Saleh,

Hazem A. Mahdy,

Mohamed Ayman El‐Zahabi

et al.

RSC Advances, Journal Year: 2023, Volume and Issue: 13(32), P. 22122 - 22147

Published: Jan. 1, 2023

A novel series of pyrimidine-5-carbonitrile derivatives bearing benzylidene and hydrazone moieties with different linkers (spacers) were designed synthesized as possible inhibitors the vascular endothelial growth factor receptor-2 (VEGFR-2). The newly compounds evaluated in vitro for their cytotoxic activities against two human cancer cell lines namely colon (HCT-116) breast (MCF-7) using sorafenib a standard anticancer drug. Compounds 9d, 11e, 12b, 12d showed higher than IC50 values ranging from 1.14 to 10.33 μM. In particular, compound 11e exhibited excellent HCT-116 MCF-7 1.54 μM, respectively. Moreover, about 47.32-fold activity normal fibroblast (WI-38) cells, lower cytotoxicity cells. 12b most potent VEGFR-2 0.61 0.53 respectively, compared sorafenib. Bedsides, arrested at S sub-G1 phases, induced significant increase apoptotic caused remarkable decrease levels TNF-α, IL-6, caspase-3. Finally, binding patterns target investigated through docking study proposed molecular (VEGFR-2, PDB ID 1YWN). results studies similar modes VEGFR-2. addition, dynamic simulations revealed stability active site 100 ns.

Language: Английский

Citations

19
Discovery of new thiazolidine-2,4-dione derivatives as potential VEGFR-2 inhibitors: In vitro and in silico studies DOI Creative Commons
Ibrahim H. Eissa, Hazem Elkady, Mahmoud Rashed

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(2), P. e24005 - e24005

Published: Jan. 1, 2024

In this study, a series of seven novel 2,4-dioxothiazolidine derivatives with potential anticancer and VEGFR-2 inhibiting abilities were designed synthesized as inhibitors. The compounds tested in vitro for their to inhibit the growth HepG2 MCF-7 cancer cell lines. Among tested, compound 22 (IC50 = 0.079 μM) demonstrated highest anti-VEGFR-2 efficacy. Furthermore, it significant anti-proliferative activities against 2.04 ± 0.06 1.21 0.04 M). Additionally, also increased total apoptotic rate lines cycle arrest at S phase. As well, computational methods applied study VEGFR-2-22 complex molecular level. Molecular docking dynamics (MD) simulations used investigate complex's structural kinetic characteristics. DFT calculations further revealed electronic properties 22. Finally, ADMET toxicity tests performed indicating likeness proposed be drugs. results suggest that displays promise an effective treatment can serve model future modifications biological investigations field.

Language: Английский

Citations

6
Synthesis, Characterizations, and Quantum Chemical Investigations on Imidazo[1,2-a]pyrimidine-Schiff Base Derivative: (E)-2-Phenyl-N-(thiophen-2-ylmethylene)imidazo[1,2-a]pyrimidin-3-amine DOI Creative Commons
Mohamed Azzouzi, Omar Azougagh,

Abderrahim Ait Ouchaoui

et al.

ACS Omega, Journal Year: 2023, Volume and Issue: 9(1), P. 837 - 857

Published: Dec. 15, 2023

In this study, (E)-2-phenyl-N-(thiophen-2-ylmethylene)imidazo[1,2-a]pyrimidin-3-amine (3) is synthesized, and detailed spectral characterizations using 1H NMR, 13C mass, Fourier transform infrared (FT-IR) spectroscopy were performed. The optimized geometry was computed the density functional theory method at B3LYP/6-311++G(d,p) basis set. theoretical FT-IR NMR (1H 13C) analysis are agreed to validate structural assignment made for (3). Frontier molecular orbitals, electrostatic potential, Mulliken atomic charge, electron localization function, localized orbital locator, natural bond orbital, nonlinear optical, Fukui functions, quantum of atoms in molecules analyses undertaken meticulously interpreted, providing profound insights into nature behaviors. addition, ADMET drug-likeness studies carried out investigated. Furthermore, docking dynamics simulations have been studied, indicating that an ideal molecule develop as a potential vascular endothelial growth factor receptor-2 inhibitor.

Language: Английский

Citations

15
In vitro and in silico evaluation of new thieno[2,3-d]pyrimidines as anti-cancer agents and apoptosis inducers targeting VEGFR-2 DOI
Souad A. El‐Metwally,

Abdelrahman A. Abuelkhir,

Hazem Elkady

et al.

Computational Biology and Chemistry, Journal Year: 2023, Volume and Issue: 106, P. 107928 - 107928

Published: July 18, 2023

Language: Английский

Citations

13
Anti-breast cancer potential of a new xanthine derivative: In silico, antiproliferative, selectivity, VEGFR-2 inhibition, apoptosis induction and migration inhibition studies DOI
Ibrahim H. Eissa, Reda G. Yousef, Hazem Elkady

et al.

Pathology - Research and Practice, Journal Year: 2023, Volume and Issue: 251, P. 154894 - 154894

Published: Oct. 14, 2023

Language: Английский

Citations

11
Immunomodulation and anticancer evaluation of quinazoline-based thalidomide analogs: Design, synthesis, docking, and dynamic simulation DOI
Abdallah E. Abdallah, Ibrahim H. Eissa,

Ahmed B. M. Mehany

et al.

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1317, P. 139082 - 139082

Published: Dec. 1, 2024

Language: Английский

Citations

4
Design, Synthesis, and Computational Evaluation of 3,4-Dihydroquinolin-2(1H)-One Analogues as Potential VEGFR2 Inhibitors in Glioblastoma Multiforme DOI Creative Commons
Shafeek Buhlak, Nadeem Abad, Jihane Akachar

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(2), P. 233 - 233

Published: Feb. 8, 2025

Background/Objectives: Glioblastoma multiforme (GBM), an aggressive and deadly brain tumour, presents significant challenges in achieving effective treatment due to its resistance current therapies poor prognosis. This study aimed synthesise evaluate 23 novel analogues of 3,4-dihydroquinolin-2(1H)-one, designed enhance druggability solubility, investigate their potential as VEGFR2 inhibitors for GBM treatment. Methods: The synthesised compounds were analysed using silico methods, including molecular docking dynamics studies, assess interactions with key residues within the binding pocket. In vitro evaluations performed on U87-MG U138-MG cell lines MTT assays determine IC50 values compounds. Results: Among tested compounds, 4u (IC50 = 7.96 μM), 4t 10.48 4m 4.20 4q 8.00 μM) demonstrated antiproliferative effects against both lines. These exhibited markedly higher efficacy compared temozolomide (TMZ), which showed 92.90 μM 93.09 U138-MG, respectively. Molecular studies confirmed strong between kinase, supporting substantial anti-cancer activity. Conclusions: highlights promising 3,4-dihydroquinolin-2(1H)-one analogues, particularly 4m, 4q, 4t, 4u, VEGFR2-targeting therapeutic agents Further detailed research is warranted validate expand upon these findings.

Language: Английский

Citations

0
Valorization of organic fruit peel wastes for Aedes aegypti control: A green chemistry approach integrating in vitro and in silico studies DOI

S Sangeetha,

Mani Poonkothai

Environmental Research, Journal Year: 2025, Volume and Issue: unknown, P. 121103 - 121103

Published: Feb. 1, 2025

Language: Английский

Citations

0
Computer-aided drug design for the double-membrane vesicle pore complex inhibitors against SARS-CoV-2 DOI Creative Commons
Han Wang, Rui Zhou, Ruolan Wang

et al.

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: March 28, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of ongoing global pandemic, has constituted worst health disaster in recent years. However, no antiviral drugs have proved clinically efficacious to combat SARS-CoV-2 infection. The double-membrane vesicle (DMV) pore complex, particularly for its positively charged residues R1613, R1614, R303, R305, and R306, which are highly conserved across β-coronaviruses play a critical role mediating RNA transport virus replication, been validated as an effective drug target. Here, we employed computer-aided design (CADD) techniques first time screen compounds against by targeting crystal structure DMV nsp3-4 complex. A total 486,387 were subjected virtual screening, such toxicity prediction, ADMET molecular docking, target analysis. six (three each binding site) selected based on their lowest energies. Notably, Compound 391 demonstrated strongest affinity R1613 R1614 at site 1, meanwhile, 5,157 exhibited most stable interactions with essential R306 2. These results demonstrate that exhibit greater potential effects, provide theoretical basis further confirmation vitro vivo studies.

Language: Английский

Citations

0