Biological assessment of new tetrahydroacridine derivatives with fluorobenzoic moiety in vitro on A549 and HT-29 cell lines and in vivo on animal model.

A new series of tetrahydroacridine derivatives with the fluorobenzoyl moiety was synthesized and evaluated for cytotoxic activity against lung cancer cell lines A549 and colorectal cancer HT29. The cytotoxic activity of the compounds was compared on the somatic cell line-EAhy926. Compounds showed high cytotoxic activity on A549 cells (IC(50) 183.26-68.07 μM) and HT29 cells (IC(50) 68.41-19.70 μM), higher than controls-etoposide (IC(50) 451.47 μM) toward A549 and 5-fluorouracil (IC(50) 1626.85 μM) against HT29. Derivative 4 was the most cytotoxic to A549, whereas for the cell lines HT29 compound 6. Selected compounds showed similar cytotoxicity to the EAhy926 cell line (IC(50) about 50 μM). In the hyaluronidase inhibition assay, all compounds exhibited anti-inflammatory activity, including 4 exhibiting the best inhibitory activity-IC(50) of 52.27 μM when the IC(50) heparin was 56.41 μM. Mathematical modeling was performed to determine LD(50) after intraperitoneal, oral, intravenous and subcutaneous administration and to predict potential mutagenicity and carcinogenicity of the compounds analyzed. Obtained results showed that tested derivatives are slightly toxic compounds, and LD(50) values (mg/kg) ranged from 680 to 1200 (oral rat model), the analyzed compounds have low mutagenic potential, and differences between derivatives are insignificant and very low probability of carcinogenicity. To confirm mathematical calculations, an in vivo test was carried out on a laboratory mouse model for two selected compounds. It allowed to qualify compounds: 6 to category 4 of the GHS scale, and 4 to category 3 of the GHS scale.