Design, Synthesis of Flurbiprofen Based 1,3,4-Oxadiazoles and Constrained Anticancer, Antioxidant Agents: In silico Docking Analysis

Flurbiprofen, a primary component of a nonsteroidal anti-inflammatory drug (NSAID) used to relieve symptoms of arthritis, and is a considerable interest in medicinal chemistry due to its demonstrated potential as an effective agent in various therapeutic applications. In consideration of the 1,3,4-oxadiazole therapeutic potential and anticancer activity, a new series of flurbiprofen scaffolds have been prepared through a straightforward reaction between 5-(1-(2-fluoro-[1,1 '-biphenyl]-4-yl)ethyl)-1,3,4-oxadiazole-2-thiol (4) and various organic active 2-chloro-N-phenyl acetamides (5). The synthesized series (6a-6k) was characterized using a combination of spectroscopic techniques, including FT-IR, mass, 1H-NMR, and 13C NMR, followed by physical data. The cytotoxicity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer cell line) and A-549 (human lung carcinoma epithelial) cell lines and anti-inflammatory activity as DPPH and H2O2 radical scavenging ability. In the series, analogues 6c, 6e, 6h, and 6k showed excellent inhibitory activity against MCF-7 cells in the range of IC50 values of 9.10-13.67 mu g mL-1 compared to DXN (IC50=9.24 mu g mL-1). In this series, analogues 6c, 6f, 6h, and 6j show remarkable H2O2 radical scavenging inhibition IC50 of 48.25 +/- 0.21, 47.33 +/- 0.15, 51.10 +/- 0.25, and 44.40 +/- 0.07 mu M by using ascorbic acid as a standard, whose IC50 is 49.90 +/- 0.27 mu M. According to the docking results, the most potent cytotoxic compounds have a stronger binding affinity with the Flurbiprofen complex (PDB: 1R9O) because of their interactions with residues such as Arg416(A), Trp103(A), Phe97(A), Gly279(A), Ile188(A), Glu283(A), Thr287(A), Val462(A), Phe459(A), Leu345(A), Ile417(A), and Cys418(A). Furthermore, in silico drug-likeness prediction analysis suggested that the majority of the synthesized compounds exhibit good oral bioavailability based on their Lipinski's Rule of Five and toxicity using ADME/Tox predictions.