Design, synthesis, and nanomedicine based delivery of benzimidazole derivatives with promising antiproliferative activity.

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

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.

Synthesis and Evaluation of Novel Piperazine Hybrids as Promising Anticancer Agents

This study aimed to synthesise a novel series of piperazine analogues (3a-k) having anticancer potential against MCF-7, MDA-MB-231 and HeLa cell lines. Structure of the synthesised analogues were confirmed through NMR and biological evaluation were done through MTT assay taking doxorubicin as a reference standard. The synthesised derivatives exhibited appreciable cytotoxicity at low concentrations. Molecular docking examined their binding interactions with estrogen receptor-α (ERα) and epidermal growth factor receptor (EGFR), associated with MCF-7 and MDA-MB-231 cell lines, respectively, providing structural insight into their anticancer potential. The results revealed that the synthesised derivative 3h has potential binding affinity hence blocking the activity. Therefore, the results obtained from in vitro and in silico studies identify the synthesised piperazine derivatives as promising lead compounds for further anticancer optimization. The IC50 values support this observation, with compounds 3g, 3h and 3i exhibiting the highest cytotoxic activity among the other derivatives evaluated.

Design, synthesis, antiproliferative evaluation, and computational studies of novel quinoline–pyrazoline hybrids against breast and ovarian cancer cell lines

Evaluation of the Antiproliferative Effects of a Newly Synthesized Benzimidazole Compound on Prostate Cancer Cells

Benzimidazole is a versatile scaffold with considerable anticancer potential due to its structural resemblance to nucleosides and its ability to function as both a hydrogen bond donor and acceptor, enabling interactions with multiple molecular targets involved in cancer progression. Numerous benzimidazole-based anticancer agents have been reported in the literature, highlighting the importance of this core structure. In this study, a novel benzimidazole derivative, SA-17, was synthesized and its anticancer activity was evaluated in the human prostate cancer cell line PC3. Cytotoxic effects were assessed in vitro using the MTT assay. Cellular proliferation was analyzed in PC3 cells following 72 hours of exposure to varying concentrations of SA-17 and the reference drug nilotinib. The results demonstrated significant differences in cell viability depending on the concentration applied. High concentrations of SA-17 (150 µg/mL and above) exhibited strong cytotoxic and antiproliferative effects against PC3 cells after 72 hours of incubation. However, nilotinib showed greater efficacy than SA-17 in reducing PC3 cell viability. Overall, the findings suggest that structural modifications of benzimidazole derivatives hold substantial potential for the development of effective anticancer agents.

Targeting breast cancer with 1,2,4-trioxanes: synthesis, cytotoxicity, and molecular docking insights

Breast cancer remains the most common malignancy among women to date, with increasing incidence and resistance to conventional therapies driving the search for novel treatments. 1,2,4-Trioxanes, known for their antimalarial activity, have emerged as promising anticancer agents due to their ability to generate reactive oxygen species (ROS) through iron-mediated activation, selectively inducing apoptosis in cancer cells. In this study, a series of hydroxy-functionalized and hemi-succinate trioxane derivatives were synthesized and evaluated against the MCF-7 breast cancer cell line. Among them, compound 10b3 showed the highest potency with an IC50 of 0.642 µM, outperforming the reference drug doxorubicin (IC50 = 0.857 µM). To complement the experimental findings, Boltz-2–guided binding affinity prediction was employed to estimate protein–ligand interaction free energies, enabling rapid and accurate assessment of binding strength beyond conventional scoring approaches. To explore the probable iron-mediated activation mechanism molecular docking experiments were further conducted to investigate binding orientation, active-site interactions, and the spatial proximity of the endoperoxide bridge to the catalytic iron atom. The compounds preferentially occupied hydrophobic pockets within the active site, stabilized mainly by hydrophobic contacts along with occasional hydrogen-bonding interactions. Notably, compound 10b3 exhibited a favourable binding orientation and interaction profile consistent with its superior in vitro activity. Density functional theory (DFT) analysis indicated that electrophilicity and electronic softness correlate with cytotoxic potency. These findings highlight the mechanistic relevance and therapeutic potential of 1,2,4-trioxanes as promising leads for further development as breast cancer therapeutics.

Evaluation of the Anticancer Potential of Nitro-Benzimidazole Derivatives in Breast Cancer.

INTRODUCTION/OBJECTIVE Breast cancer is the most common malignancy among women worldwide, and the emergence of resistance to anthracycline-based chemotherapy remains a major clinical challenge. Benzimidazole scaffolds have attracted considerable interest in medicinal chemistry due to their broad pharmacological properties and anticancer potential. This study aimed to investigate the anticancer activity, selectivity, and molecular mechanisms of novel nitro-benzimidazole derivatives in luminal and Adriamycin-resistant breast cancer cell lines. METHODS A series of benzimidazole derivatives was synthesized and evaluated using in silico pharmacokinetic analyses. Cytotoxicity was assessed by MTT assay in MCF-7, adriamycinresistant MCF-7 (MCF-7/Adr), and normal human fibroblast cells CCD-1072sk. The most active compound was further investigated by RT-qPCR-based gene expression and pathway enrichment analyses, flow cytometry-based evaluation of apoptosis and cell cycle distribution, fluorescence-based morphological analyses, and gene-metabolite interaction analysis. RESULTS Among the tested compounds, SN-1 exhibited the strongest antiproliferative activity, with IC₂⁽ values of 4.86 ± 0.27 μM in MCF-7 cells and 8.62 ± 1.51 μM in MCF-7/Adr cells, along with a high selectivity index. SN-1 significantly induced apoptosis and caused cell cycle arrest at the G2/M phase in MCF-7 cells and at the G0/G1 phase in MCF-7/Adr cells. Gene enrichment and metabolite interaction analyses revealed modulation of apoptosis-, cell cycle-, and metabolism-related pathways, including associations with glycerol, ATP, and ADP. DISCUSSION These findings suggest that SN-1 exerts selective anticancer activity against both drug-sensitive and chemoresistant breast cancer cells through the regulation of apoptosis, cell cycle progression, and metabolic pathways. The observed effects on resistant cells further indicate the therapeutic potential of SN-1 in overcoming chemotherapy resistance. CONCLUSION The nitro-benzimidazole derivative SN-1 exhibits strong and selective anticancer effects in both drug-sensitive and chemoresistant breast cancer cells by modulating apoptosis, cell cycle progression, and key metabolic pathways.