Synthesis of flurbiprofen thiadiazole urea derivatives and assessment of biological activities and molecular docking studies

Totally 15 novel flurbiprofen urea derivatives were synthesized bearing the thiadiazole ring. Their inhibition effects on tyrosinase were determined. 3c was found to be the strongest inhibitor with the IC50 value of 68.0 mu M against tyrosinase. The enzyme inhibition types of the synthesized compounds were determined by examining the kinetic parameters. The inhibition type of 3c was determined as uncompetitive and the K-i value was calculated as 36.3 mu M. Moreover, their cytotoxic effects on hepatocellular carcinoma (HepG2), colorectal carcinoma (HT-29), and melanoma (B16F10) cell lines were evaluated. According to the cytotoxicity results, 3l (IC50 = 14.11 mu M) showed the highest cytotoxicity on the HT-29 cells, while 3o (IC50 = 4.22 mu M) exhibited the strongest cytotoxic effect on HepG2 cell lines. Also, 3j (IC50 = 7.55 mu M strongly affected B16F10. The effects of synthesized compounds on the healthy cell line were evaluated on the CCD-986Sk cell line. Molecular modelling studies have indicated the potential binding interactions of the uncompetitive inhibitor 3c with the enzyme-substrate complex.

Automated summary

Fifteen novel flurbiprofen urea derivatives containing the thiadiazole ring were synthesized and tested for their inhibition effects on tyrosinase. Compound 3c was found to be the most potent inhibitor with an IC50 value of 68.0 μM. The synthesized compounds were also evaluated for their cytotoxic effects on different cancer cell lines, and 3l showed the highest cytotoxicity on HT-29 cells, 3o exhibited the strongest cytotoxic effect on HepG2 cells, and 3j strongly affected B16F10 cells.