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 ?g/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.