Design, synthesis, and nanomedicine based delivery of benzimidazole derivatives with promising antiproliferative activity.
TL;DR
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.
Abstract
The growing global challenge posed by cancer, alongside its consistently high mortality rates, underscores the urgent need for innovative therapeutic agents that can effectively tackle its intricate pathophysiology and enhance patient survival rates. This study explores two series of benzimidazole based derivatives designed and synthesized as potential antiproliferative agents. The synthesized derivatives were screened for antiproliferative activity against cancer cell lines MCF7, MDA-MB-231, A549, HCT-116, and HEPG2. Cytotoxicity was assessed on normal VERO cells to ensure compound safety. The synthesized candidates were further evaluated for their potential TrkA enzyme inhibition. Compound 16a exhibited potent antiproliferative activity, especially against MCF7 and A549 cell lines, surpassing sorafenib and tamoxifen as reference drugs, with robust growth inhibition across multiple cancer cell lines. It achieved IC50 values of 1.62 μM on MCF7 and 3.65 μM on A549 cells, while also showing the highest activity against the TrkA enzyme among the synthesized derivatives (IC50 = 15.01 μM). Cellular mechanistic studies revealed that 16a induced a pronounced G1-phase arrest in MCF7 cells (79.58% vs. 59.27% in doxorubicin; the positive control), accompanied by significant promotion of both apoptosis and necrosis. This was coupled with a pronounced upregulation of pro-apoptotic proteins, including Bax, cytochrome-c, and caspase-9, together with a significant downregulation of anti-apoptotic regulators such as Bcl-2 and AKT-1 in comparison to doxorubicin. To enhance antiproliferative efficacy and optimize physicochemical properties, compounds 16a and 17b from both series were entrapped in human serum albumin nanoparticles, resulting in four optimized formulations (A16a, B16a, A17b, and B17b). Characterization via dynamic light scattering and transmission electron microscopy confirmed successful nanoparticle preparation. Substantial potency improvements were exhibited: A16a achieved a ten-fold enhancement in MCF7 cells (1.62 μM to 0.11 μM), while B17b improved activity by fourteen-fold (19.6 μM to 1.43 μM). Most formulations preserved the wide safety margin demonstrated against normal VERO cells. Collectively, 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.