engleski

The impact of structure changes of nicotinamide derivates on cholinesterase inhibition and cytotoxicity

Nicotinamide derivatives have broad pharmacological properties especially as inhibitors of many enzymes involved in pathogenesis of numerous illnesses. They are investigated for such as anticancer, anti- angiogenic and antinociceptive agents, but also as drugs for treating patients with neurodegenerative Alzheimer’s disease (AD). In that sense, we investigated a series of nine nicotinamide derivatives as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and tested their potential cytotoxic effect on human cells. Namely, since AD is characterized by reduced level of cerebral neurotransmitter acetylcholine, drug design for the treatment of AD based on cholinesterases inhibition, to prevent present acetylcholine from being degraded fast, may have clinical benefits in alleviating the manifestation of disease. As our results show, all nine tested nicotinamide derivatives inhibited both cholinesterases in μM range, with up to 50- times higher preference for binding to AChE. Structural modifications, in terms of substituents change, had influenced both AChE and BChE inhibition equally. The most pronounced negative effect on the affinity of the enzymes for binding of these derivatives, in terms of determined inhibition constant Ki, was observed when -Cl or - Br were introduced, e.g. instead of fluorine, into the core structure. On the other hand, the most effective inhibitor of both cholinesterases (AChE Ki = 3.5 μM ; BChE Ki = 8 μM) was aromatic 1-(2- ([1, 10-Biphenyl]-4-yl)-2-oxoethyl)-3- carbamoylpyridin-1-ium bromide, pointing to specific properties of the cholinesterases’ active site. The cytotoxic effect to human neuronal and kidney cells was observed for four derivatives having -Cl, -Br, -NO2 or -Ph substituents. Even though this result has its negative implications, overall inhibition profile of tested nicotinamide derivatives encourages the use of such scaffold for structure refinement process and further consideration in development of more efficient cholinesterase inhibitors. Acknowledgment: This work was supported by the Croatian Science Foundation under project UIP- 2017-05-7260 and IP- 2018-01-7683.

nicotinamide ; cholinesterase ; inhibition ; cytotoxicity ; Alzheimer’s disease

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