Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition

Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)-approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro investigation of the anticancer activity of a series of novel thiazolyl-hydrazones based on the 8-quinoline (1a-c), 2-quinoline (2a-c), and 8-hydroxy-2-quinolyl moiety (3a-c). The panel of several human cancer cell lines and the nontumorigenic human embryonic kidney cell line HEK-293 were used to evaluate the compound-mediated in vitro anticancer activities, leading to [2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)]-4-(4-methoxyphenyl)-1,3-thiazole (3c) as the most promising compound. The study revealed that 3c blocks the cell-cycle progression of a human colon cancer cell line (HCT-116) in the S phase and induces DNA double-strand breaks. Also, our findings demonstrate that 3c accumulates in lysosomes, ultimately leading to the cell death of the hepatocellular carcinoma cell line (Hep-G2) and HCT-116 cells, by the mechanism of autophagy inhibition. A series of quinoline-based thiazolyl-hydrazones was synthesized and evaluated for antiproliferative activity. The most promising compound, 2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)-4-(4-methoxyphenyl)-1,3-thiazole (3c), accumulates in lysosomes, halts cell-cycle progression at the S phase and induces DNA double-strand breaks, indicating the importance of the 2-hydroxy-8-hydroxyquinoline fragment for targeting cancer cells via autophagy inhibition.image

Automated summary

Heterocyclic pharmacophores such as thiazole and quinoline rings play an important role in medicinal chemistry. This study focuses on the synthesis and evaluation of a series of novel thiazolyl-hydrazones based on quinoline and hydroxyquinoline moieties. The most promising compound, 2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)-4-(4-methoxyphenyl)-1,3-thiazole (3c), shows significant anticancer activity by blocking cell-cycle progression, inducing DNA double-strand breaks, and inhibiting autophagy.