No abstract

Alzheimer's disease is an irreversible and progressive brain disease that can cause problems with memory and thinking skills. It is characterized by loss of cognitive ability and severe behavioral abnormalities, and could lead to death. Cholinesterases (ChEs) play a crucial role in the control of cholinergic transmission, and subsequently, the acetylcholine level in the brain is upgraded by inhibition of ChEs. Coumarins have been shown to display potential cholinesterase inhibitory action, where the aromatic moiety has led to the design of new candidates that could inhibit Aβ aggregation. Accordingly, the present work is an in vitro activity, along with docking and molecular dynamics (MD) simulation studies of synthesized coumarin derivatives, to explore the plausible binding mode of these compounds inside the cholinesterase enzymes. For this purpose, a series of previously prepared N1 -(coumarin-7-yl) derivatives were screened in vitro for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. The assayed compounds exhibited moderate inhibitory activity against AChE, with IC 50 values ranging from 42.5 ± 2.68 to 442 ± 3.30 μM. On the other hand, the studied compounds showed remarkable activity against BChE with IC 50 values ranging from 2.0 ± 1.4 nM to 442 ± 3.30 μM. In order to better understand the ligand binding site interaction of compounds and the stability of protein-ligand complexes, a molecular docking with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases. We concluded that the tested coumarin derivatives are potential candidates as leads for potent and efficacious ChEs inhibitors.

A series of new N1-(coumarin-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-amino-4-methylcoumarin with the appropriate piperazines. The chemical structures of the newly prepared compounds were supported by elemental analyses, 1H-NMR, 13C-NMR, and ESI-HRMS spectral data. The antitumor activity of the newly synthesized compounds was evaluated. Among all the compounds tested, 7-{2-[1-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-yl)-2-oxopropylidene]hydrazinyl}-4-methyl-2H-chromen-2-one (3n) was the most potent against MCF-7 and K562 cells, with IC50 values of 20.2 and 9.3 μM, respectively.

No abstract

Herein, we have synthesized and tested a selected set of N1-(coumarin-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-ones (8) incorporating masked α-amino acids within the triazinone skeleton as synthetic fluorogenic substrates for amino peptidases using human nasal epithelium that expressed aminopeptidases. These chiral triazinones, obtained via direct interaction of α-amino esters with N1-(coumarin-7-yl) nitrile imine (generated in situ from its hydrazonoyl chloride by the action of triethylamine), bear close resemblance to 7-amino-4-methylcoumarin (AMC) with labeled α-amino acids (AA-AMC's/7). The aminopeptidase activity of the synthesized compounds (0.125 and 0.5 mM) was compared with that of a model compound L-alanine-4-methylcoumaryl-7-amide (Ala-MCA), following in-house validation of the aminopeptidase activities of the human nasal primary culture. In comparison to the model aminopeptidase substrate (Ala-MCA), the synthesized compounds yielded fluorescent 7-amino-4-methylcoumarin following incubation with nasal epithelial cells. However, the yield was significantly lower than was observed for the control compound.