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

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
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
Integrated in silico and in vitro exploration of the anti-VEGFR-2 activities of a semisynthetic xanthine alkaloid inhibiting breast cancer DOI Creative Commons
Eslam B. Elkaeed, Hazem Elkady, Ahmed M. Khattab

et al.

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0316146 - e0316146

Published: Jan. 27, 2025

This study presents T-1-NBAB , a new compound derived from the natural xanthine alkaloid theobromine, aimed at inhibiting VEGFR-2, crucial protein in angiogenesis. ’s potential to interacts with and inhibit VEGFR-2 was indicated using silico techniques like molecular docking, MD simulations, MM-GBSA, PLIP, essential dynamics, bi-dimensional projection experiments. DFT experiments utilized also structural electrostatic properties of . Computational analysis performed predict ADME-Tox profiles After semisynthesis, vitro results showed that effectively inhibits an IC 50 0.115 μM, compared sorafenib’s 0.0591 μM. In tests demonstrated significant activity against breast cancer cell lines MCF7 T47D, values 16.88 μM 61.17 respectively, high selectivity. Importantly, induced early late apoptosis cells, indicating its as strong anticancer agent. Additionally, reduced migration healing abilities suggesting it could be promising anti-angiogenic Overall, these findings suggest is lead for further research treatment cancer.

Language: Английский

Citations

0
Anti-breast cancer potential of thieno-pyrimidine derivatives as VEGFR-2 inhibitors DOI
Aisha A. Alsfouk, Maged Mohammed Saleh Al Ward,

Mustafa A. Al-Qadhi

et al.

Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: March 17, 2025

Background Thieno-pyrimidine derivatives have emerged as promising candidates for VEGFR-2 inhibition. This study aimed to design, synthesize, and evaluate novel thieno-pyrimidine their anti-cancer potential.

Language: Английский

Citations

0
Design and synthesis of thiadiazoles as anticancer, apoptotic, and VEGFR-2 inhibitors DOI
Walid E. Elgammal, Hazem Elkady, Mohammed A. Dahab

et al.

Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: April 8, 2025

Vascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 with promising anticancer activity. The synthesized compounds were evaluated for anti-proliferative activity against human cell lines (HCT-116, MCF-7, and HepG-2), WI-38 normal cells. Sorafenib was used reference drug. inhibitory determined, followed by cycle analysis, apoptosis assays, Q-RT-PCR wound-healing assays. In silico molecular docking conducted explore binding interactions. Among the tested compounds, 13b exhibited potent (IC50: 3.98-11.81 µM) strong inhibition 41.51 nM), surpassing sorafenib 53.32 nM). Cell analysis revealed that induced G2/M phase arrest MCF-7 Apoptosis levels increased from 2% 52%, accompanied > 12-fold rise Bax/Bcl-2 ratio activation caspase-8/9. Additionally, significantly suppressed migration, only 5.28% wound closure. studies confirmed its Thiadiazole-based derivatives, particularly compound 13b, exhibit inhibition, effects, induction, anti-migratory activity, supporting agents.

Language: Английский

Citations

0
Targeting VEGFR-2 in breast cancer: synthesis and in silico and in vitro characterization of quinoxaline-based inhibitors DOI Creative Commons
Ibrahim H. Eissa, Alaa Elwan,

Mustafa A. Al-Qadhi

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(17), P. 12896 - 12916

Published: Jan. 1, 2025

Design, synthesis and in vitro silico studies of novel quinoxaline-based derivatives as antitumor VEGFR-2 inhibitors with apoptotic activities.

Language: Английский

Citations

0
Nicotinamide Loaded Chitosan Nanocomplex Shows Improved Anticancer Potential: Molecular Docking, Synthesis, Characterization and In vitro Evaluations DOI
Ahmed M. Metwaly, M.A. Abu-Saied,

Ibraheem M. M. Gobaara

et al.

Current Organic Chemistry, Journal Year: 2024, Volume and Issue: 28(1), P. 46 - 55

Published: Jan. 1, 2024

Abstract: This study aimed to prepare and characterize chitosan nanoparticles encapsulating a nicotinamide derivative (Ni-CS-NP). Additionally, the therapeutic effectiveness, cytotoxicity, selectivity, immunomodulatory properties of Ni-CS-NP were evaluated in human breast colon cancer cell lines. Chitosan have shown potential as drug delivery carriers due their biocompatibility controlled release properties. Encapsulating further enhances these nanoparticles. Computational studies employed validate binding interactions, providing crucial insights into formulation's stability effectiveness. The primary objective was assess cytotoxicity safety profiles Moreover, this investigate specific mechanisms underlying its cytotoxic effects, including impact on cycle progression, apoptosis induction, immunomodulation. synthesized using ionic gelation method characterized Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission (TEM), thermo gravimetric analysis. lines through MTT assay. Selectivity indices calculated determine profiles. inhibition VEGFR-2, induction apoptosis, disruption, effects assessed molecular assays. analysis demonstrated favorable interactions complex. characterization confirmed successful synthesis with well-defined structural thermal exhibited remarkable superior profile against MCF7 HCT 116 showing IC50 values 2.32 2.70 μM, respectively, surpassing sorafenib's efficacy (IC50 = 4.12 7.55 respectively). effectively inhibited induced both early late disrupted progression cells. Notably, significant by reducing TNF-α IL-2 levels compared dexamethasone. encapsulation within (Ni-CS-NP) proved successful. displayed potent profiles, promising These findings highlight novel agent for treatment, warranting investigation clinical applications.

Language: Английский

Citations

3
Design, synthesis, in vitro, and in silico studies of new thiadiazol derivatives as promising VEGFR-2 inhibitors and apoptosis inducers DOI

Hazem A. Mahdy,

Hazem Elkady, Walid E. Elgammal

et al.

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1316, P. 139019 - 139019

Published: June 19, 2024

Language: Английский

Citations

3
Rationale design and synthesis of new apoptotic thiadiazole derivatives targeting VEGFR-2: computational and in vitro studies DOI Creative Commons
Walid E. Elgammal, Hazem Elkady,

Hazem A. Mahdy

et al.

RSC Advances, Journal Year: 2023, Volume and Issue: 13(51), P. 35853 - 35876

Published: Jan. 1, 2023

This work presents the synthesis and in vitro, silico analyses of new thiadiazole derivatives that are designed to mimic pharmacophoric characteristics vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. A comprehensive evaluation inhibitory properties synthesized against cancer cell lines MCF-7 HepG2 identified several auspicious candidates. Among them, compound 14 showed remarkably low IC50 values 0.04 μM 0.18 HepG2, respectively. VEGFR-2 revealed a promising value nanomolar range (103 nM). Further examination cycle has ability stop progression cells via G0-G1 phase arrest. Interestingly, also demonstrated noteworthy pro-apoptotic effect cells, with notable increases early apoptosis (16.53%) late (29.57%), along slight increase population necrotic (5.95%). Furthermore, significant drop cells' migrate heal wounds. Additionally, promoted by boosting BAX (6-fold) while lowering Bcl-2 (6.2-fold). The binding affinities candidates their target were confirmed computational investigations, including molecular docking, principal component analysis trajectories (PCAT), dynamics (MD) simulations. 14's stability reactivity investigated using density functional theory (DFT). These thorough results highlight potential as lead contender for additional research creation anticancer drugs VEGFR-2. establishes foundation future therapeutic developments anticancer- angiogenesis-related scientific fields.

Language: Английский

Citations

8
Novel Thiazolidine‐2,4‐Dione Derivatives as Potential VEGFR‐2 Inhibitors: Synthesis, Biological Testing, and in Silico Studies DOI
Ibrahim H. Eissa, Hazem Elkady, Mohammed S. Taghour

et al.

ChemistrySelect, Journal Year: 2024, Volume and Issue: 9(11)

Published: March 15, 2024

Abstract In this work novel 2,4‐dioxothiazolidine‐derived compounds targeting VEGFR‐2 were designed and synthesized. Such evaluated for their anti‐proliferative inhibitory abilities. Compound 17 specifically demonstrated the strongest activity against HCT‐116 cell line, with an IC 50 value of 10.09 μM. Additionally, 15 , 18 19 revealed good effects values 12.46, 16.87, 12.35 μM, respectively. potent anti‐VEGFR‐2 efficacy, 0.068 which was comparable to sorafenib (IC 0.058 μM). induced apoptosis in cancer cells caused G0‐G1 phase cycle arrest. Furthermore, it upregulated BAX levels (5.1‐fold) downregulated Bcl‐2 (4.2‐fold), indicating its pro‐apoptotic effects. also increased caspase‐8 caspase‐9 by 3.3‐fold 4.7‐fold, respectively, compared control. The computational studies provided insights into kinetic, structural properties, binding mode VEGFR‐2‐ complex. DFT calculations elucidated compound ′s electronic while ADMET toxicity tests suggested acceptable degrees drug‐likeness potential synthesized compounds. Our findings suggest that holds promise as a apoptotic inhibitor may guide future efforts developing new anticancer drugs.

Language: Английский

Citations

2