Development of Benzothiophene-Bearing Bis-oxadiazole Derivatives for Potential Anticancer Targets: Evaluation of DFT, ADME-Tox, and In Silico Docking.

Combining two pharmacophores into one molecule with multiple applications presents interest in the field of medicinal chemistry. Benzo[b]thiophenes are among privileged scaffolds due to their wide biological activities, whereas oxadiazoles are versatile linkers with pharmacological potential. Thus, this article focused on the synthesis of novel benzo[b]thiophene-linked bis-oxadiazoles and the exploration of their anticancer potential. The structural elucidation of the prepared oxadiazole compounds was established by 1H NMR, 13C NMR, and HRMS spectroscopic analysis. The in vitro anticancer activity effect on the human colorectal (HT-29, HCT-116 and Caco-2) and breast (MDA-MB-231) cancer cell lines was assessed for each synthesized compound. It was revealed that compounds 7b and 7g showed well-established anticancer affinities on HT-29 and Caco-2 cell lines with inhibitory concentrations of 6.2 ± 0.67 and 8.1 ± 0.89 µg/mL in comparison to the reference drug etoposide (IC50 = 7.5 ± 1.04 and 9.5 ± 1.01 µg/mL). Notably, compound 7i displayed the highest antiproliferative activity among the tested compounds, with selectivity towards the MDA-MB-231, IC50 9.5 ± 0.38 µg/mL, with respect to Etoposide (IC50 = 8.4 ± 0.91 µg/mL). Ligand 7i showed the best docking score (-9.92 kcal*mol-1), followed by ligand 7 g (-10.68 kcal*mol-1), with favorable H-bonding residues GlnA:64, AsnA:103, GlnA:112 and SerA:111 within the colorectal active site (PDB code: 2HQ6). DFT analyses elucidated electronic properties, including geometry optimization, frontier molecular orbitals, and EHOMO-ELUMO (0.12766-0.15523 eV), correlating with observed bioactivity. The theoretical predictions by DFT and in silico docking and ADMET-physicochemical properties were well supported by the experimental studies and revealed strong anticancer activity. Collectively, these findings highlight the benzo[b]thiophene scaffold as a highly promising candidate for the development of new anticancer inhibitors, warranting further investigation.