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  • Phenylbenzofurans are a very important molecule skeleton due


    Phenylbenzofurans are a very important molecule skeleton due to their synthetic versatility and their proved pharmacological properties [2]. They are synthetic compounds in which an additional phenyl ring is present in any position of the benzofuran nucleus. This could be easily obtained possible by two principal general methods: by a C-phenylation of a benzofuran [3] or by the construction of the benzofuran nucleus with the new ring already included on it [4]. In the present work we describe the second method, by a classical Wittig reaction [5], [6], perhaps the most direct and general method known for preparing the desired 2-phenylbenzofurans. Recently, benzofuran derivatives have showed enzymatic inhibition properties for example on monoamine oxidase [7], acetylcholinesterase (AChE) [8], [9], [10] and butyrylcholinesterase (BChE) [11], [12]. Acetylcholine (ACh) is a neurotransmitter that plays a role in the modulation of memory function in normal and neurodegenerative conditions [13]. In the cholinergic system, disruption in the levels of ACh is caused by hydrolytic action of cholinesterases (ChEs), a family of LY2109761 sale that play a role in ACh regulation and in the cholinergic signaling [14]. AChE and BChE appear to be simultaneously active in the synaptic hydrolysis of ACh, terminating its neurotransmitter action, and co-regulating levels of ACh. A well-documented strategy to restore the neurotransmitter level involves the use of cholinesterase inhibitors that suppress the ChEs enzymes and therefore increasing both the level and duration of the neurotransmitter action [15], [16], [17]. In our efforts to contribute to the development of novel compounds that may be useful in the treatment of neurodegenerative disorders such as Parkinson’s disease (PD) or Alzheimer’s disease (AD), we are focusing on 2-phenylbenzofuran derivatives [7], [11], [12], [18], [19]. In particular, with the aim of finding out structural features in the ChEs inhibitory activity, in the present work, we describe the synthesis of hydroxylated 2-phenylbenzofuran derivatives 7-bromine and 7-chlorine substituted and the importance of hydroxyl groups substitution in the 2-phenyl ring. We recently developed a series of 2-phenylbenzofurans which exhibited selective inhibitory property for BChE enzyme. Considering that the 7-chlorine-2-(3,5-dihydroxyethoxyphenyl)benzofuran and 7-bromine-2-(3,5-dihydroxyethoxyphenyl)benzofuran displayed highest inhibitory activity towards BChE with IC50 values of 6.23 μM and 3.57 μM respectively [11], [12], in this paper we studied the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring in addition to the presence of a halogen at positions 7 of the benzofuran scaffold, which has been revealed as adequate position for substitution.
    Result and discussion
    Conclusion In this study, we have used the Wittig reaction as a key step for the efficient and general synthesis of a series of hydroxylated 2-phenylbenzofuran derivatives. All the compounds have been evaluated for their cholinesterase inhibitory activity. The experimental results showed that most of the benzofurans tested are selective BChE inhibitors with a varying efficiency. The IC50 values of BChE inhibition indicated compounds 6 and 8 with the presence of bromine at position 7 of the benzofuran scaffold as the most potent inhibitors with an IC50 value of 7.96 and 10.86 µM respectively. However, a thorough analysis of the results obtained, revealed that the maximum inhibitory activity was displayed by benzofurans derivatives with two hydroxyl substituents in meta position on the phenyl-ring and chlorine and bromine atoms respectively at position 7 of benzofuran scaffold (compounds 11 and 12). Thus, our study provides a complete picture of the importance of number and position of the hydroxyl groups in the 2-phenyl ring, and among the compounds tested, two hydroxyl substituents in meta position to be the most functional for the cholinesterase inhibition. Moreover, comparative physicochemical and pharmacokinetic properties of the compounds with the commonly prescribed drugs revealed high LY2109761 sale probability of all the compounds to be absorbed in the brain and exhibiting promising druglikeness characteristics. Finally, molecular docking simulations assisted in explaining the structure-activity relationships of this type of compounds.