Substituted 2-arylquinoline and 2-methyl-1,2,3,4-tetrahydroquinoline derivatives with selective anticancer activity: synthesis, structure–activity relationships, and molecular modelling insights†

In this study, a series of nineteen 2-arylquinolines and 4-acetamido-2-methyl-1,2,3,4-tetrahydroquinolines 4–22 was prepared using Povarov reaction protocols and their in vitro cytotoxicity was tested against human cancer cell lines, HeLa, PC3, MCF-7, and SKBR-3, compared with human dermis fibroblasts as non-tumor cells. In general, these quinoline derivatives displayed compelling selective anticancer properties. It was found that the 2-arylquinoline derivatives 4–16 displayed a better activity profile against the cell lines evaluated than the 2-acetamido-2-methyl-THQs 17–22. Particularly, C-6 substituted 2-phenylquinolines 4–10 and 2-(3,4-methylenedioxyphenyl)quinolines 11–16 displayed important activities against the evaluated cell lines, highlighting the results obtained generally against PC3 and HeLa. At the same time, MCF-7 and SKBR-3 cells were much less sensitive to them. Quinoline 13 and tetrahydroquinoline 18 showed selective cytotoxicity with IC₅₀ values of 8.3 μM and 13.15 μM, respectively, in cervical epithelial carcinoma, while quinolines 12 and 11 displayed good cytotoxicity with considerable IC₅₀ values (31.37 and 34.34 μM) in prostate sarcoma. All these compounds (except 11) stand out due to their low unspecific cytotoxicity presenting a remarkable selectivity (SI = 36.21–113.08) compared to doxorubicin. According to the ADME profiling, aromatic quinolines 4–16 are more lipophilic molecules (c Log P = 2.23–4.13) than partially saturated THQ compounds 17–22 (cLogP = 1.56–3.02), but all quinoline derivatives are more lipophilic molecules than the doxorubicin drug (cLogP = 0.48). The relationship between the lipophilicity (cLogP) and cytotoxic effects (IC₅₀), especially in HeLa and PC3 cells, the quinolines 4–16 with greater octanol/water partition coefficients showed better IC₅₀ values in HeLa and PC3 cells, contrasting with the THQs 17–22 which displayed lower cLogP values and poor activity. Molecular docking studies of most active quinoline compounds 4,5 and 10–14 against tested cancer cell lines and KDM5A, KDM4B, KDM4A, and HER-2 proteins revealed good correlations between the IC₅₀ values exhibited by these molecules and their binding interaction strength suggesting that they could be promising selective regulators of the KDM proteins.