Background:
The well-known antibacterial agent Triclosan (TCL) that targets bacterial
enoylacyl protein reductase has been described to inhibit human fatty acid synthase (FASN) via
the enoylacyl reductase domain. A Literature survey indicates that TCL is selectively toxic to cancer
cells and furthermore might indeed reduce cancer incidence in vivo. A recent study found that
TCL inhibits FASN by acting as an allosteric protein-protein interface (PPI) inhibitor. It induces
dimer orientation changes that effect in a downstream reorientation of catalytic residues in the
NADPH binding site proposing TCL as a viable scaffold to design a superior molecule that might
have more inhibitory potential. This unveils tons of potential interaction space to take advantage of
future inhibitor design.
Objective:
Synthesis of TCL mimicking novel diphenyl ether derivatives, biological evaluation as
potential antiproliferative agents and molecular docking and molecular dynamics simulation studies.
Methods:
A series of novel N-(1-(3-hydroxy-4-phenoxyphenyl)-3-oxo-3-phenylpropyl)acetamides
(3a-n) and N-(3(3-hydroxy-4phenoxyphenyl)-3-oxo-1-phenylpropyl) acetamides (6a-n) were designed,
synthesized, characterized and evaluated against HepG2, A-549, MCF-7 and Vero cell
lines. The induction of antiproliferative activity of selected compounds (3d and 6c) was done by
AO/EB (acridine orange/ethidium bromide) nuclear staining method, DNA fragmentation study,
and cell cycle analysis was performed by flow cytometry. Molecular docking and dynamics simulation
study was also performed.
Results:
Among the tested compounds, compound 3d was 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. 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 for calculating binding
free energies using Molecular Mechanics–Generalized Born Surface Area (MM/GBSA).
Conclusion:
Compound 3d (IC50 13.76 ± 0.43 µM) has been identified as a potential lead molecule
for anticancer activity against A-549 cells followed by 3l, 6c, and 3g. Thus, the design of
diphenyl ether derivatives with enhanced affinity to the binding site of hER may lead to the discovery
of potential anticancer agents.
Integrated 3D-QSAR, molecular docking and molecular dynamics simulation studies on 1,2,3-triazole based derivatives for designing new acetylcholinesterase inhibitors
