In this work, BTEAC (
benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-
oxadiazole scaffolds BF1-9. These bromobenzofuran-
oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-
hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key
cancer targets, such as EGFR, PI3K, mTOR, GSK-3β, AKT, and
Tubulin polymerization
enzymes. Bromobenzofuran structural motifs BF-2, BF-5, and
BF-6 displayed the best anti-
cancer potential and with the least cell viabilities (12.72 ± 2.23%, 10.41 ± 0.66%, and 13.08 ± 1.08%), respectively, against HepG2
liver cancer cell line, and they also showed excellent molecular docking scores against EGFR, PI3K, mTOR, and
Tubulin polymerization
enzymes, which are major
cancer targets. Bromobenzofuran-
oxadiazoles BF-2, BF-5, and
BF-6 displayed excellent binding affinities with the active sites of EGFR, PI3K, mTOR, and
Tubulin polymerization
enzymes in the molecular docking studies as well as in MMGBSA and MM-
PBSA studies. The stable bindings of these structural hybrids BF-2, BF-5, and
BF-6 with the
enzyme targets EGFR and PI3K were further confirmed by molecular dynamic simulations. These investigations revealed that 2,5-dimethoxy-based bromobenzofuran-
oxadiazole BF-5 (10.41 ± 0.66% cell viability) exhibited excellent cytotoxic therapeutic efficacy. Moreover, computational studies also suggested that the EGFR, PI3K, mTOR, and
Tubulin polymerization
enzymes were the probable targets of this BF-5 scaffold. In silico approaches, such as molecular docking, molecular dynamics simulations, and DFT studies, displayed excellent association with the experimental
biological data of bromobenzofuran-
oxadiazoles BF1-9. Thus, in silico and in vitro results anticipate that the synthesized bromobenzofuran-
oxadiazole hybrid BF-5 possesses prominent anti-
liver cancer inhibitory effects and can be used as lead for further investigation for anti-HepG2
liver cancer therapy.