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  • In the context of our ongoing studies to

    2021-05-06

    In the context of our ongoing studies to define the phytochemical and biological properties of oxyprenylated secondary metabolites of plant and fungal origin, we wish to report herein the investigation on the interaction of some natural and semisynthetic O-alkylcoumarins with promising ChE inhibitory effect by in vitro and in silico approaches. On this purpose, 26 products (Fig. 1) have been tested in vitro against AChE and BChE using high-throughput screening system, while the active inhibitors were proceeded to in silico experiments (Table 2, Table 3, Fig. 2, Fig. 3, Fig. 4). The natural sources of compounds 1–4, 9, 11, 14, 15, 23 and 24 have been described previously [8]. All other coumarins have been obtained by chemical synthesis. Briefly, the parent hydroxycoumarins were alkylated with the respective alkyl bromide or iodide in acetone and in the presence of dry K2CO3 as the ci-1033 at 80 °C for 1 h (Scheme 1).
    Materials and methods
    Results and discussion
    Conclusion In the current study, 26 O-alkylcoumarin derivatives were tested for their cholinesterase inhibitory activity and 12 of them displayed a noteworthy inhibition towards BChE. Among them, the best inhibitory compound was revealed to be 7-styryloxycoumarin (IC50 = 7.01 ± 0.28 µM) by both in vitro screening and in silico experiments. Structure-activity relationship considerations led to hypothesize that ci-1033 introduction of lipophilic moieties as substituents alternative to free OH groups represents an effective means to increase the inhibitory activities on ChE. This kind of structural substitution has first a deep influence on the pharmacokinetic properties of herein synthesized coumarins in respect to native OH free compounds. Pharmacokinetic data in fact showed that all compounds have lipophilic character and permeate blood brain barrier (BBB). This may have a great potential considering that putative ChE inhibitors may be used as pharmacologically active agents against severe neurological disorders. The binding energy values calculated using docking simulations are favorable and suggested that strong polar and nonpolar interactions were formed between the ligand atoms and the active site amino acids of BChE. Thus, a second important acquisition from our studies is that the presence of large, bulky, and conformationally rigid moieties provide substituted coumarins having a greater selectivity towards BChE. Such a result may arise from a tight interaction of the styryl moiety with a specific aminoacidic portion of the active site of BChE.
    Conflicts of interest
    Introduction Cholinesterase inhibitors (ChI) represent a broad group of chemical substances with their primary site of action being the acetylcholinesterase enzyme (AChE). It is important to distinguish between reversible inhibitors, which are used in therapy of glaucoma [1], myasthenia gravis treatment [2], as antidotes [3], for symptomatic treatment of Parkinson’s and Alzheimer’s diseases [4,5], and the irreversible or quasi-irreversible inhibitors some of which are used as insecticides, such as parathion, malathion or carbofuran [6]. However, several of these substances possess a dangerous potential of chemical warfare agents, namely sarin, soman and tabun used for their high volatility and extraordinary toxicity. Their action is based on esterification of a serine hydroxyl group found in the active center of the AChE [7]. This results in modification of the AChE, leaving it without its biological role and effectively preventing the enzyme from breaking down the acetylcholine molecule. Accumulation of acetylcholine at the receptor sites disrupts the cholinergic neurotransmission system with consequent prolonged excessive stimulation of cholinergic receptors [8]. Some of the clinical consequences according to the location, type, exposure method and absorbed doses, can be muscarinic, nicotinic and also show central clinical symptoms. Depending on the dose and substance type this can lead to a lethal acute cholinesterase inhibitor toxicity (acute cholinergic crisis) [9], typically resulting in a failure to breathe due to paralyzed smooth muscles [10].