Synthesis and biological evaluation of thiophene based oxadiazole derivatives as promising anticancer agents against liver cancer.

BACKGROUND

Liver cancer is a leading cause of cancer-related mortality worldwide. Clinical use of the first-line drug sorafenib is limited due to drug resistance and severe adverse effects.

OBJECTIVES

The current study aimed to synthesize a series of N-arylated thiophene-based 1,3,4-oxadiazole derivatives containing a carbamothioate moiety (7a-7d) as potential anticancer agents with improved efficacy and safety profiles.

METHODS

Derivatives were synthesized via coupling of thiophene-based 1,3,4-oxadiazole (compound 1) with various electrophiles, yielding 62-86%. The structures of all derivatives were established based on FT-IR, 1H NMR, 13C NMR, and EI-MS. The in-vitro anticancer effect of all derivatives was assessed using the MTT assay against the HepG2 cancer cell line and their hemolytic safety was assessed on human red blood cells.

RESULTS

All derivatives exhibited cytotoxicity with minimal hemolytic effects. Derivative 7b (2,6-dimethyl) exhibited excellent activity by reducing cell viability of 33.96 ± 2.47% at 100 μg/mL and minimal hemolysis (1.20 ± 0.01%) with a high selectivity index (SI) of 28.3, similar to sorafenib (34.32 ± 1.91%, SI = 27.45). Derivatives 7a (phenyl) and 7d (ethyl) showed moderate activity and 7c (fluoro) was the least potent.

CONCLUSION

Thiophene-based oxadiazole-coupled carbamothioate derivatives, particularly 7b, demonstrate enhanced anticancer efficacy and safety compared to sorafenib, representing promising candidates for targeted liver cancer therapy.