Synthesis, in vitro and in silico anticancer evaluations of novel styryl 1,3,4-oxadiazole-sulfonamide hybrids for colorectal cancer

Abstract

Colorectal cancer (CRC) remains a major contributor to cancer mortality, necessitating novel therapeutic strategies to overcome drug resistance and the adverse effects of current chemotherapeutics. This study aimed to synthesize a new series of styryl-1,3,4-oxadiazole-sulfonamide hybrids and to evaluate their cytotoxicities in vitro, stability of protein-ligand complex, druggability, and solubility properties in silico to find out their potential as an effective anticancer agent for CRC treatment. An efficient multistep approach was used involving a facile reduction of 4-nitrophenyl substituted styryl-1,3,4-oxadiazoles to yield corresponding anilines (10a-e), which were subsequently converted into benzenesulfonamides (11a-o). All title compounds were obtained in high yields and characterized using FTIR, NMR, and HRMS analysis. The newly synthesized anilines (10) and sulfonamides (11) were then evaluated for their antiproliferative activities against CRC cell lines, HCT116 and SW48. The results of in vitro studies revealed significant cytotoxic potential of some compounds such as 10a, 10c, 11f, 11h, 11i, and 11l showing potent activity (IC₅₀ < 25 μM). In particular, compound 11c exhibited the strongest activity (IC₅₀: 18.47 μM), which is slightly better than reference drug daunorubicin (IC₅₀: 22.91 μM) against HCT116 cell lines. Furthermore, molecular docking and dynamic simulations studies confirmed the strong interactions between the compounds (10,11) and TNIK kinase protein, underpinning their significant anticancer effects. The findings highlight that styryl-1,3,4-oxadiazole aniline derivatives, particularly 11c, 11f, 11h, 11i, 11l, and 11m, may be TNIK-targeted candidate molecules for CRC treatment and show encouraging potential. Further experimental tests against specific TNIK proteins may need to confirm and extend these findings.