Toxicological profiling of a de novo synthesized benzimidazole derivative with potent and selective proapoptotic potentials against breast cancer

• Published in: Food and chemical toxicology Vol. 180; p. 114049
• Main Authors: Farrag, Ebtehal K., Aziz, Wessam M., Shaker, Sylvia E., Shawky, Heba, Fayed, Dalia B.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.10.2023
• Subjects: Antioxidant; Apoptosis; Benzimidazole; Breast cancer; Cytotoxicity; G0/G1 phase arrest; Cytotoxicity; G0/G1 phase arrest; Breast cancer; Antioxidant; Benzimidazole; Apoptosis
• DOI: 10.1016/j.fct.2023.114049
• ISSN: 0278-6915

This study aimed to investigate the toxicological profile of 1-(6-(1H-benzo[d]imidazole-2-yl)-2-methylpyridin-3-yl) ethanone (BMPE), both in vitro and in vivo. The proapoptotic/necrotic and cell cycle arrest potentials of BMPE were assessed in MCF-7 cell line. The in vivo toxicology was assessed in female Balb/c mice by repeated dosing of 5, 25, and 50 mg/kg for 21 consecutive days, then different biochemical, inflammatory, and oxidative markers were assessed in sera/tissue homogenates of treated animals. The new derivative showed a potent selective cytotoxicity against malignant cell lines with IC50 value 0.2 μM/mL, while the cytotoxic effect on normal Wi-38 cells was observed at IC50 value 0.4 μM/mL; i.e. twofold the effective anticancer dose. BMPE exhibited an early DNA fragmentation-derived cell apoptosis observed at the G0/G1 checkpoint. In vivo, BMPE was biochemically/immunologically tolerable at a pharmacological dose range of 5–25 mg/kg, with no significant rates of mortality/morbidity and minimal-to-moderate histopathological alterations recorded. The new derivative represents an attractive therapeutic candidate for breast cancer, considering its noticeable modulatory effect on the oxidative-inflammatory axis that would relate to its potent antitumor effect. [Display omitted] •BMPE showed a selective cytotoxicity against MCF-7 cells with IC50 value < 0.2 μM/mL.•The IC50 value of BMPE on normal cells was twofold the effective anticancer dose.•BMPE induced early DNA-fragmentation-derived cell apoptosis at the G0/G1 checkpoint.•BMPE is well tolerable in-vivo within a pharmacological dose range of 5–25 mg/kg.•BMPE exhibited exceptional modulatory effect on the oxidative-inflammatory axis.