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

Abstract

AbstractFlurbiprofen, 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 μg mL−1 compared to DXN (IC50=9.24 μg 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 μM by using ascorbic acid as a standard, whose IC50 is 49.90±0.27 μM. 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.