Diverse C-6 substituted 4-methyl-2-(2-, 3- and 4-pyridinyl)quinolines: synthesis, in vitro anticancer evaluation and in silico studies

A series of twelve 4-methyl-2-(2-, 3- and 4-pyridinyl)quinolines 7–9 was synthesized using modified Kametani reaction protocol and their in vitro cytotoxicity was tested against human cancer cell lines MCF-7, SKBR-3, PC3, HeLa, comparing with human dermis fibroblast as non-tumor cells. In general, these molecules displayed potent anticancer properties, but also demonstrated a narrow safe margin, as it was observed for doxorubicin. Compounds 8a, 8b, 9a and 9d showed prominent selective cytotoxicity with higher IC50 values compared with reference drug doxorubicin in prostate carcinoma, cervical epithelial carcinoma and breast carcinoma (no overexpresses the HER2/c-erb-2 gene), respectively. The 4-methyl-2-(3-pyridinyl)quinoline (8a) stands out by its low unspecific cytotoxicity (IC50 = 476.69 μM) and highly exceptional selectivity for PC3 cells (IC50 = 4.40 μM) as an interesting model for antitumor drugs against prostate carcinoma. Its 4-pyridinyl analog 9a showed superior potency against HeLa cells (IC50 = 0.016 μM) and an outstanding selectivity (SI = 4168.1) compared to doxorubicin (IC50 = 3.62 µM, SI = 0.7). Analog 9d revealed potent activity (IC50 = 0.38 µM) against breast cancer MCF-7. In silico studies are also reported. ADME profiling, in silico toxicity and drug-score data of compounds 8a and 9a resulted to be favorable compared to doxorubicin.