Abstract
This work reports the synthesis and evaluation of a new series of Dichlorobenzyloxy-chalcone scaffolds 95(a-i). The synthesis started with the O-alkylation of hydroxybenzaldehydes (1, 8, and 13) using dimethylformamide as a solvent and potassium carbonate as a catalyst at room temperature, producing the ether intermediates 7, 92, and 93, each containing a 3,4-dichlorobenzyloxy group. These intermediates were reacted with acetophenones (94) through a Claisen-Schmidt condensation using ethanol as a solvent and 40% NaOH as a catalyst, yielding α,β-unsaturated carbonyl compounds 95(a–i). The compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, and mass spectrometry. The in vitro biological evaluations showed noticeable differences in activities across the series. Antibacterial evaluation demonstrated that 95i was the most effective compound against Gram-negative E. coli, with a minimum inhibitory concentration (MIC) of 0.13 ± 0.00 mg/mL. In contrast, 95e, 95f, and 95i were the most effective against Gram-positive S. aureus, each with an MIC of 0.17 ± 0.07 mg/mL. Among the derivatives, compound 95a exhibited the highest radical scavenging activity in the DPPH assay, while compound 95h showed strong anticancer activity against both MCF-7 and HCT116 cell lines. In addition, various in silico studies were performed, including ADME, density functional theory (DFT), and molecular docking, which helped interpret the electronic properties and possible interaction modes of the compounds. Linear regression analysis was conducted to relate biological activities with quantum chemical parameters, including EHOMO, ELUMO, solubility (Log S), and lipophilicity (Log P). Overall, the results suggest that introducing a 3,4-dichlorobenzyloxy group, along with suitable substituent modification, improves hydrophobicity and hence membrane permeability. This approach may therefore be useful for enhancing the therapeutic potential of chalcone-based compounds.
