Design, Synthesis, and In Silico Evaluation of Novel Benzimidazole-Based Urea Derivatives Targeting VEGFR-2

Integrated In Silico and In Vitro Discovery of a VEGFR-2-Targeted Anticancer Benzanilide Lead

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.

Tetrazole–imidazole hybrid derivatives as potential EGFR tyrosine kinase inhibitors: design, synthesis and in silico evaluation with preliminary antiproliferative assessment

Integrated design, synthesis, biological evaluation, and computational mechanistic insights of novel benzanilide derivatives as VEGFR-2 targeted anticancer agents

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.

1-Butylindoline-2,3-dione derivatives as potent VEGFR-2 inhibitors: synthesis, mechanistic anticancer studies, and molecular dynamics simulations

A novel series of N-butyl isatin (indolin-2-one) derivatives was designed and synthesized as potential VEGFR-2-targeted anticancer agents, drawing inspiration from the oxindole-based inhibitor sunitinib. The synthesized compounds were assessed for antiproliferative activity against colorectal cancer cell lines (HT29 and HCT116) and for their inhibitory potential on VEGFR-2. Compound 6b exhibited the highest potency, demonstrating strong VEGFR-2 inhibition comparable to that of sunitinib. Mechanistic investigations in HCT116 cells demonstrated that 6b induced G0/G1 cell cycle arrest and promoted apoptosis, which was associated with the upregulation of p53 and Bax, downregulation of Bcl-2, and suppression of Cyclin D1 and Cyclin E expression. Furthermore, 6b markedly decreased VEGF-A expression, supporting modulation of VEGF/VEGFR-2-associated signaling. Molecular docking studies involving VEGFR-2 (PDB ID: 4AGD) demonstrated favorable binding of compound 6b in the ATP-binding pocket, establishing essential interactions with essential residues. Docking validation was established through the successful redocking of sunitinib, yielding an RMSD of 0.44 Å. Additionally, 500 ns molecular dynamics simulations indicated stable backbone behavior, regulated ligand fluctuations, preserved structural compactness, and sustained hydrogen bonding within the 6b-VEGFR-2 complex. The findings collectively identify compound 6b as a promising lead candidate for further development as a VEGFR-2-targeted anticancer agent.

Design, Synthesis, and Exploration of Biological Activities of Novel Benzoxazole Derivatives through In-silico and In vivo Approaches.

INTRODUCTION Many natural and synthetic compounds have been investigated for their anti-inflammatory and analgesic properties, but most of them possess significant adverse effects. The versatility of benzoxazole derivatives allows for the design of compounds with specific target interactions. Structural modifications may lead to the development of more efficacious and safer drugs for various medical conditions. METHOD A series of substituted benzoxazole compounds was synthesized, yielding six (E)-1-[4-{2- (benzo[d]oxazol-2-yl)phenylamino}phenyl]-3-(substituted phenyl)prop-2-en-1-ones, denoted as 3a-3f, and further characterized by IR, NMR, and mass spectroscopic methods. The synthesized derivatives were tested for anti-inflammatory and analgesic activities using animal models. The binding interactions of the synthetic compounds with the targets were investigated through a molecular docking study using Schrodinger Maestro version 2022-4. Molecular dynamics (MD) simulation was performed for 50 ns to investigate the protein's characteristics, monitor internal molecular transformations, and assess the long-term stability of the protein-ligand complex. RESULTS All the compounds exhibited significant anti-inflammatory and analgesic activities at a dose of 100 mg/kg compared to Diclofenac. In in silico studies, the compounds exhibited the required binding interactions and stability. DISCUSSION The docking studies indicated that the compound substituted with 3-hydroxyphenyl (3c) behaved as a COX-1 inhibitor. The simulated complexes of 3c with COX-1 and COX-2 demonstrated stability throughout the simulation, with RMSD values of 3.5 Å and 4 Å, respectively. CONCLUSION The present research would pave the way for researchers to synthesize more benzoxazole derivatives devoid of significant adverse effects using novel approaches.

SYNTHESIS, MOLECULAR DOCKING, AND ANTICANCER ACTIVITY OF NOVEL COUMARIN DERIVATIVES

Coumarin scaffolds are attractive templates for anticancer drug discovery because they modulate multiple molecular targets, including receptor tyrosine kinases, apoptosis regulators, and topoisomerases. This study aimed to synthesize, characterize, and evaluate three novel coumarin derivatives: 3-(4-fluorophenyl)-7-hydroxycoumarin (C1), 3-(3,4-dimethoxyphenyl)-7-methoxycoumarin (C2), and 6-bromo-3-(4-chlorophenyl) coumarin (C3). The compounds were synthesized using modified Pechmann or Knoevenagel condensation routes, purified by column chromatography, and characterized by FTIR, UV–Vis, 1H/13C NMR, LC–MS/MS, HRMS, elemental analysis, melting point, and TLC. Molecular docking was performed against EGFR, VEGFR-2, PI3K, CDK2, Bcl-2, and Topoisomerase II using validated protein structures, while drug-likeness and ADMET properties were predicted using SwissADME, pkCSM, and ADMETlab. Anticancer activity was assessed by MTT assay against MCF-7, A549, HeLa, and HCT-116 cell lines. The compounds were obtained in 58–74% yields with confirmed structures. C1 demonstrated the strongest binding toward EGFR (−9.1 kcal/mol) and Bcl-2 (−8.0 kcal/mol), forming key interactions with Met793 and hydrophobic residues, and exhibited the highest cytotoxicity against MCF-7 (IC₅₀ = 6.8 ± 0.9 µM) and HCT-116 (IC₅₀ = 9.5 ± 1.1 µM). C2 preferentially targeted CDK2 and PI3K, whereas C3 showed favorable binding to Topoisomerase II and VEGFR-2 with selective activity against A549 cells (IC₅₀ = 8.9 ± 1.2 µM). ADMET analysis predicted favorable oral drug-likeness for C1 and C2 with acceptable pharmacokinetic profiles. Overall, C1 emerged as the most promising lead for further optimization as a multitarget anticancer agent, while C2 and C3 provide complementary scaffolds for future medicinal chemistry and mechanistic investigations.