Findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
Abstract
VEGFR-2 is a key regulator of tumor angiogenesis and a validated target in anticancer drug discovery. In this study, a series of novel benzanilide derivatives (7a–7f and 9a–9b) were designed, synthesized, and evaluated as potential VEGFR-2 inhibitors. The design strategy was guided by key pharmacophoric requirements for VEGFR-2 inhibition. All compounds were synthesized successfully and characterized, then screened for in vitro cytotoxic activity against MCF-7, MDA-MB-231, HePG-2, and HCT-116 cancer cell lines, with WI-38 and WISH normal cells used for selectivity assessment. Among the tested compounds, 7e emerged as the most potent derivative, exhibiting IC50 values ranging from 8.49 to 11.21 µM across cancer cell lines, comparable to sorafenib. Importantly, 7e also demonstrated favorable selectivity toward cancer cells with a promising selectivity index profile. Mechanistic studies revealed that compound 7e significantly inhibited VEGFR-2 kinase activity (IC50 = 1.79 ± 0.05 µM), supporting its targeted anti-angiogenic mechanism. Flow cytometry analysis showed that 7e induced G0/G1 cell cycle arrest and markedly increased apoptotic cell populations. This was further confirmed by upregulation of Bax, Caspase-3, and Caspase-8, alongside downregulation of Bcl-2, indicating activation of both intrinsic and extrinsic apoptotic pathways. Interestingly, 7e inhibited cancer cell migration, suggesting a potential anti-angiogenetic effect. Density functional theory (DFT) calculations revealed that 7e possesses a conjugated electronic system with a suitable frontier orbital distribution, moderate HOMO–LUMO gap, and a favorable electrostatic potential for receptor interaction. Molecular docking and dynamics simulations demonstrated stable binding of 7e within the VEGFR-2 active site, supported by consistent RMSD, hydrogen bonding, and compact structural behavior. MM-GBSA calculations confirmed favorable binding free energy, while per-residue decomposition and protein–ligand interaction fingerprint analysis identified key stabilizing interactions. Essential dynamics and free energy landscape mapping further confirmed a stable and energetically favorable conformational state. ADMET and toxicity predictions indicated acceptable pharmacokinetic properties, low mutagenic risk, and an overall favorable safety profile. Collectively, these findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
A rational pharmacophore-guided strategy was employed to design and synthesize a series of novel coumarin derivatives as potential dual cyclin-dependent kinase 6 (CDK6) and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Following structural characterization, the synthesized compounds were evaluated for their anticancer activity against MCF-7, MDA-MB-231, HepG-2, and HCT-116 cancer cell lines, together with normal WI-38 and WISH cells. Among the tested derivatives, compound 7e exhibited the highest potency, with IC50 values ranging from 3.80 to 6.35 µM, while demonstrating superior selectivity toward cancer cells compared with sorafenib. Enzymatic assays confirmed potent dual inhibition of VEGFR-2 (IC50 = 0.3905 µM) and CDK6 (IC50 = 0.3380 µM). Mechanistic studies revealed that compound 7e induced significant apoptosis, promoted S-phase cell cycle arrest, and effectively inhibited cell migration in HCT-116 cells. Computational studies, including molecular docking, molecular dynamics simulations, and binding free energy calculations, supported its stable interactions with both kinase targets. Furthermore, in silico ADMET analysis predicted favorable pharmacokinetic and safety profiles. Collectively, these findings identified compound 7e as a promising dual VEGFR-2/CDK6 inhibitor with potent and selective anticancer activity, warranting further preclinical investigation.
Hazem Elkady, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, Celina Nazareth et al.· Journal of the Iranian Chemi...· 0 citations
These findings highlight benzimidazole derivatives, particularly 16a and 17b and their nanoparticle formulations, as promising anticancer candidates, driven primarily by strong cellular potency and favorable safety, substantiating their potential as lead candidates for further optimization and therapeutic development.
Mai Montaser Abdullah, R. Hathout, Reham S. Elezaby et al.· RSC Medicinal Chemistry· 0 citations
The results revealed that the synthesised derivative 3h has potential binding affinity hence blocking the activity, and the synthesised piperazine derivatives are identified as promising lead compounds for further anticancer optimization.
Vaibhav Daund, Pooja Agarwal, A. Jain et al.· Asian Journal of Chemistry· 0 citations
This study aimed to develop novel CDK2 inhibitors with potent antimelanoma activity. Accordingly, a series of 2‐thioxothiazolyl pyrazoles (2–11) was rationally designed through molecular hybridization and synthesized using efficient and straightforward synthetic procedures. The structures of the synthesized compounds were confirmed by IR, NMR, mass spectrometry, and elemental analyses. All compounds were evaluated by the NCI, USA, against the 60‐human cancer cell line panel at a single dose (10 µM). The preliminary screening revealed promising antiproliferative activity, particularly against melanoma cell lines, with compound
11
exhibiting the highest growth inhibition against LOX‐IMVI and MALME‐3 M cells (21.60% and 49.41%, respectively). Based on these results, compounds
2, 4,
and
11
were further evaluated by the MTT assay. Compound
11
exhibited the greatest cytotoxicity, with IC
50
values of 3.82 and 2.52 µM against LOX‐IMVI and MALME‐3 M cells, respectively, superior to doxorubicin and 5‐fluorouracil, together with excellent selectivity (SI = 12.14 and 18.40). Moreover, compound
11
potently inhibited CDK2 (IC
50
= 1.07 µM), approaching the activity of roscovitine (IC
50
= 0.84 µM), and induced cell cycle arrest at G1‐phase, besides promoting intrinsic apoptosis (23‐ to 40‐fold) in MALME‐3 M cells. These findings identify compound
11
as a promising selective CDK2‐targeted lead for melanoma therapy.
A. Hassan, S. El‐Sebaey, Moshira A. El Deeb et al.· ChemistrySelect· 0 citations
The development of selective vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors remains a promising strategy for anticancer therapy targeting tumor angiogenesis. In the study at hand, a novel benzanilide-based derivative, ACEB-Cl, was rationally designed by assimilating fundamental pharmacophoric characteristics essential for VEGFR-2 inhibition. ACEB-Cl was evaluated using a comprehensive approach that combined computational modeling, synthesis, and in vitro biological assessment. Density functional theory (DFT) calculations revealed a favorable electronic profile, with distinct nucleophilic and electrophilic regions that could support potential interactions within the VEGFR-2 binding pocket. Docking and molecular dynamics (MD) simulations suggested stable binding of ACEB-Cl within the ATP-binding pocket, supported by strong hydrophobic interactions and favorable binding free energy (ΔG = −63.21 kcal/mol). Following synthesis, ACEB-Cl confirmed potent anti-VEGFR-2 activity in an ELISA-based assay (IC50 = 0.086 0.002 M), showing higher potency than sorafenib. Western blot analysis further confirmed significant downregulation of phosphorylated VEGFR-2 in MDA-MB-231 cells. In vitro cytotoxicity studies revealed selective anticancer activity, with reduced toxicity toward normal Vero cells and favorable selectivity indices. Mechanistically, ACEB-Cl triggered G0/G1 phase arrest and significantly increased apoptotic cell death, highlighting its ability to suppress cancer cell proliferation. Additionally, ADMET and toxicity estimations indicated a balanced pharmacokinetic and safety profile, with improved solubility, acceptable absorption, and reduced toxicity risks compared to sorafenib. Overall, this integrated study pinpointed ACEB-Cl as a promising VEGFR-2targeted anticancer lead compound with strong inhibitory potency, and a clearly defined mechanism of action, supporting its progression for further improvement.
A. Metwaly, I. Eissa, Walid E. Elgammal et al.· Journal of Computational Bio...· 0 citations