engleski

Synthesis and biological evaluation of 4-amino-7- chloroquinolines as novel reversible inhibitors of human cholinesterases

4-Aminoquinolines are a class of compounds known mostly as antimalarials, among which chloroquine, hydroxychloroquine and amodiaquine are the most used drugs. These compounds also have antiinfective and anti-inflammatory activity and have been successfully used for the treatment of certain autoimmune diseases. Due to their ability to cross the blood-brain barrier, they have attracted attention as potentially CNS active agents. In our pilot study, we determined the ability of eight 4- aminoquinolines differing in the substituents attached to the C(4)-amino group and C(7) to inhibit the activity of human acetyl- and butyrylcholinesterases, the main targets in developing drugs for treating Alzheimer’s disease (AD). In continuation of our studies, we pointed out two major goals: the first to explore the impact of length, conformational flexibility, steric demands, basicity and electronic density of the linker between aminoquinoline moiety and terminal amino group, and the second to explore the impact of different N- terminus substituents, as are adamantane or substituted benzyl, on the inhibition of human acetyland butyrylcholinesterase. Starting from the corresponding 4- chloroquinoline and using different alkyl- (normal or branched) or aryldiamines, in various solvents (net diamine, phenol, NMP or EtOH) and heating in the inert atmosphere, corresponding 4- aminoquinolines were obtained. Further modifications of the terminal amino group by reductive amination yielded two series of derivatives that have N-benzyl or Nadamantyl moieties. Alternatively, previously synthesized side chains were directly coupled with the corresponding 4- chloroquinoline. Structure-activity analysis revealed that n- octenyl as a linker is favourable for the inhibition of both acetyl- and butyrylcholinesterase, without pronounced selectivity toward either. Docking studies rationalized our kinetic results and provided us insight into potential ligand-enzyme interactions. An in silico evaluation of ligand’s ability to cross the blood-brain barrier and their drug- likeness was also evaluated.

acetylcholinesterase ; butyrylcholinesterase ; 4-amino-7-chloroquinolines ; drug-likeness ; flexible docking ; Alzheimer`s disease

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