Synthesis, characterization, and in silico studies of new benzohydrazide derivatives targeting EGFR kinase

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

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

regulated primarily via vascular endothelial growth factor receptor-2 (VEGFR-2). Although VEGFR-2 is a confirmed target in anti-tumor management, available inhibitors currently suffer from many limitations such as drug resistance and dose-related toxicity, so it becomes necessary to develop novel and more safe inhibitors. The aim of this study is to design, synthesize, and evaluate a new series of benzimidazole-urea derivatives (U1–U4) as potential inhibitors of VEGFR-2 with enhanced binding affinity and better drug-likeliness properties. Methods: Four compounds benzimidazole-urea derivatives were synthesized chemically and analyzed structurally using FT-IR, 1H-NMR, and 13C-NMR spectroscopy. Molecular docking studies were performed against VEGFR-2 (PDB ID: 4ASD) to detect interaction profiles especially binding affinity, with Sorafenib which is used as a reference inhibitor. Physico-chemical properties and pharmacokinetics (ADME) properties were predicted to evaluate drug-likeness and oral bioavailability. Statistical analysis used. Docking scores and binding energies were obtained from molecular docking simulations and analyzed in comparison with the reference drug; no experimental statistical tests were applied. Results: The four synthesized derivatives exhibited high binding affinities toward VEGFR-2. The best among them were compound U4 which showed the highest docking score (−9.8877 kcal/mol), better than that of Sorafenib (−9.3847 kcal/mol). We identified the key interactions with critical amino acid residues, including Glu885, Asp1046, and Cys919, which indicating stable binding within the ATP-binding pocket. More interesting result were in silico ADME analysis that revealed beneficial physicochemical properties and expected oral bioavailability for all the four synthesized compounds. Conclusion: The newly synthesized benzimidazole-urea derivatives exhibit potential VEGFR-2 inhibitory activity, favourable binding properties and drug likeliness. These compounds are promising and could be more extensively tested in biological systems as anti-angiogenic and anticancer drugs.

Design and Synthesis of 2,4-Thiazolidinedione-Based Derivatives as Potent EGFR-Targeting Anticancer Agents

A series of quinoline- and naphthalene-based 2,4-thiazolidinedione (TZD) hybrids (5a–5o) were rationally designed and synthesized using a pharmacophore hybridization approach targeting epidermal growth factor receptor (EGFR). The synthesized compounds were evaluated for in vitro antiproliferative activity against human cancer cell lines including MDA-MB-453, A549, PC-3, and MCF-7, along with EGFR inhibitory activity. Several compounds exhibited promising cytotoxicity, with derivatives 5c, 5f, 5g, and 5n showing significant activity (IC₅₀ = 4.6–9.8 µM). Molecular docking studies using EGFR crystal structures (PDB: 1M17 and 4HJO) demonstrated favorable binding affinities and key interactions with the ATP-binding pocket, particularly hydrogen bonding with Met793. Docking results correlated well with experimental EGFR inhibition, supporting an EGFR-mediated mechanism. Structure–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity. These findings identify TZD hybrids as promising EGFR-targeted anticancer leads.

In Silico Exploration of Novel EGFR T790M and C797S Resistance with Mutant-Selective Allosteric Inhibitors Using a Hybrid Computational Approach

Synthesis, characterization, molecular docking and pharmacokinetics of new pyrimidine carboxylate derivatives as potent VEGFR inhibitors

Purpose: To investigate the strategic design and synthesis of three new pyrimidine carboxylate derivatives aimed at inhibiting VEGFR signaling pathways to suppress tumor growth. Methods: A set of 3 new pyrimidine carboxylate derivatives was successfully synthesized via optimized chemical routes. Structural integrity of the synthesized compounds was characterized using advanced spectroscopic techniques, including FT-IR, 1H-NMR, and 13C-NMR. Furthermore, multidimensional in silico investigations were conducted to evaluate therapeutic potential. Results: According to the simulation of molecular docking, the three derivatives demonstrated a high potential for bonding in the vascular endothelial growth factor receptor (VEGFR) active site forming stable complex structures through a series of key hydrogen bond and hydrophobic interactions between important amino acid residues. Additionally, complete ADMET profiling indicated that the three compounds have excellent pharmacokinetic profiles and high oral bioavailability. Conclusion: This study shows that the synthesized pyrimidine carboxylates bind effectively with VEGFR active site, demonstrate favourable pharmacokinetic properties and high oral bioavailability. Keywords: 

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.