Synthesis, biological evaluation and molecular dynamics simulation studies of novel diphenyl ethers

A series of novel N-(1-(3-hydroxy-4-phenoxyphenyl)-3-oxo-3-phenylpropyl)acetamides and N-(3(3-hydroxy-4phenoxyphenyl)-3-oxo-1-phenylpropyl) acetamides were designed, synthe-sized, and evaluated against HepG2, A-549, MCF-7 and Vero cell lines. Among the tested com-pounds, compound 3d was the most active (IC50 13.76 ± 0.43 µM) against A-549 cell line. Compounds 3d and 3g were found to be moderately active with IC50 30.56 ± 1.1 µM and 25.05 ± 0.8 µM respectively against MCF-7 cell line. Induction of antiproliferative activity of compound 3d and 6c was confirmed by AO/EB (acridine orange/ethidium bromide) nuclear staining method and also by DNA fragmentation study. Morphological analysis of A-549 cells treated with 3d and 6c clearly demonstrated the reduction of cell viability and induction of apoptosis. DNA fragmentation was observed as a characteristic of apoptosis in treated cells. Further, cell cycle analysis by flow cytometry confirmed that compounds 3d and 6c significantly arrested the cell cycle at the G0/G1 phase. Molecular docking study demonstrated that these compounds exhibit high affinity for the human fatty acid synthase (hFASN) target. Molecular dynamics simulation study of the most active compound 3d was performed by calculating binding free energies using Molecular Mechan-ics–Generalized Born Surface Area (MM/GBSA).