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

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 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.