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

Synthesis of novel nicotinic acid derivatives of potential antioxidant and anticancer activity DOI
Yara El‐Dash, Nadia A. Khalil, Eman Ahmed

et al.

Archiv der Pharmazie, Journal Year: 2023, Volume and Issue: 356(12)

Published: Oct. 4, 2023

This study comprises the design and synthesis of novel nicotinic acid-based cytotoxic agents with selective inhibitory efficacy against vascular endothelial growth factor receptor-2 (VEGFR-2). Screening compounds for cytotoxicity was assessed 60 human cancer cell lines. The two most active compounds, 5b 5c, reference drugs sorafenib doxorubicin were investigated HCT-15, PC-3, CF-295 Compound 5c exhibited highest potential compared to HCT-15 PC-3 tumor Moreover, it higher selectivity toward panel sorafenib. demonstrated promising VEGFR-2 inhibition (concentration needed inhibit viability by 50%, IC50 = 0.068 μM) superior over epidermal receptor platelet-derived receptor-β enzymes. It also reduced total phosphorylated induced apoptosis, as evidenced a 4.3-fold rise in caspase-3 levels. antioxidant new determined via measuring superoxide dismutase (SOD) levels, among which compound an SOD level almost comparable ascorbic acid. These results suggested that dual activities. Docking into pocket showed similar binding mode ADME (absorption, distribution, metabolism, excretion) profile outlined drug-likeness. Finally, density functional theory calculations displayed increased affinity target enzyme.

Language: Английский

Citations

4
Design and In Silico and In Vitro Evaluations of a Novel Nicotinamide Derivative as a VEGFR-2 Inhibitor DOI Creative Commons
Ibrahim H. Eissa,

Muhammad Abd ElGayed Bkrah,

Reda G. Yousef

et al.

Journal of Chemistry, Journal Year: 2024, Volume and Issue: 2024, P. 1 - 25

Published: March 1, 2024

A new nicotinamide derivative, (E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazone)ethyl)phenyl)nicotinamide, was designed as a VEGFR-2 inhibitor. Utilizing the density functional theory (DFT) calculations, three-dimensional structure of compound determined, shedding light on its stability and reactivity. Molecular docking revealed capability to inhibit VEGFR-2, which further supported by molecular dynamics (MD) simulations confirming binding target protein. In addition, mechanics-generalized born surface area (MM-GBSA), protein-ligand interactions profiler (PLIP), essential studies provided validation compound’s precise with optimal energy. Then, “compound 10” synthesized subjected in vitro assays. Compound 10 inhibited an IC50 value 105.4 ± 0.896 nM, comparing sorafenib’s 61.65 0.934 nM. Besides, it exhibited cytotoxicity against HepG2 MCF-7 cancer cell lines, values 35.78 0.863 μM 57.62 0.871, 5.95 0.917 8.45 0.912 μM. Furthermore, demonstrated lower level toxicity towards Vero 127.3 Likewise, induced apoptosis lines through flow cytometric analysis addition increase levels caspase-3 caspase-9. Moreover, hindered migration healing abilities cells. conclusion, our study positions promising candidate for chemical modifications biological evaluations.

Language: Английский

Citations

1
Pyridazinone based derivatives as anticancer agents endowed with anti-microbial activity; Molecular design, synthesis, and biological investigation DOI

Mohamed K.S. El-Nagar,

Mai I. Shahin, Mohammed Farrag El‐Behairy

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(10), P. 3529 - 3557

Published: Jan. 1, 2024

Discovery of novel pyridazinone derivatives with dual antimicrobial and anticancer activities.

Language: Английский

Citations

0
Phthalazine Derivatives as VEGFR‐2 Inhibitors: Docking, ADMET, Synthesis, Design, Anticancer Evaluations, and Apoptosis Inducers DOI Open Access

Hatem Hussein Bayoumi,

Mohamed‐Kamal Ibrahim,

Mohammed A. Dahab

et al.

Drug Development Research, Journal Year: 2024, Volume and Issue: 86(1)

Published: Dec. 24, 2024

New phthalazine-derived inhibitors for VEGFR-2 were synthesized anticancer evaluations. Also, docking studies performed to explore the suggested binding orientations of novel derivatives inside site VEGFR-2. The achieved biological data extremely interrelated that study. In specific, derivative 3f was greatest effective compound against HepG2 and MCF-7 cancer cell lines with IC

Language: Английский

Citations

0
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

Citations

0