A New Class of Benzo[ <i>b</i> ]Thiophene‐1,3,4‐Oxadizole Bearing 1,2,4‐Oxadiazoles as Potent Antimicrobial Targets: Synthesis, Biological Evaluation, Docking, DFT and ADMET Studies

ABSTRACT Benzo[ b ]thiophene‐1,3,4‐oxadizole and 1,2,4‐oxadiazole hybrids 9a – 9l were tested against both antibacterial and anticancer, revealing interesting structure–activity relationships. The structure of all of the synthesized products was exhaustively established by proton, carbon NMR, and HRMS analyses. In general, benzothiophene bearing bis ‐oxadiazole scaffolds from series 9 proved to be better inhibitors of both activities, with compound 9g being the best bacterial inhibitor (MIC = 4.12 µM) on Klebsiella pneumonia and compound 9c being the excellent bacterial inhibitor on Streptococcus pneumonia (MIC = 4.75 µM), the last one having an MIC better than reference compound delafloxacin (MIC = 5.02 µM). Notably, compounds 9c , 9g displayed the highest anticancer activity among the tested compounds, with selectivity towards the HepG‐2 cell line IC 50 values of 4.10 ± 0.37, and 4.25 ± 0.26 µg/mL, with respect to the reference drug DXN (IC 50 = 4.57 ± 0.20 µg/mL). Electronic characteristics of all synthesized hybrid compounds were accessed via density functional theory calculations (DFTs) at the B3LYP/6–311++G (d,p). In fact, the ligand‐ 9k had the most negative ΔG (−10.23 kcal/mol), which showed favorable interactions with the key amino acid residues at the active site of K. pneumonia receptor (PDB code: 6JYY). Drug‐likeness properties were predicted at the end via ADME‐Tox analysis, to support the investigations.