Structural Insight of New Butyrylcholinesterase Inhibitors Based on Benzylbenzofuran Scaffold

Abstract

In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds that displayed a selective inhibitory activity for BChE. Here, in an effort to discover novel selective BChE inhibitors with favorable physicochemical and pharmacokinetic profiles, 2-benzylbenzofurans were designed, synthesized, and evaluated as BChE inhibitors. The 2-phenylbenzofuran scaffold structure is modified by introducing one methylene spacer between the benzofuran core and the 2-phenyl ring with a hydroxyl substituent in the para or meta position. Either position 5 or 7 of the benzofuran scaffold was substituted with a bromine or chlorine atom. Further assessment of the selected list of compounds indicated that the substituent's nature and position determined their activity and selectivity. 5-bromo-2-(4-hydroxybenzyl)benzofuran 9B proved to be the most potent butyrylcholinesterase inhibitor (IC₅₀ = 2.93 µM) of the studied series. Computational studies were carried out to correlate the theoretical and experimental binding affinity of the compounds to the BChE protein.

Keywords: benzylbenzofuran; butyrylcholinesterase inhibitors; docking studies.

Scheme 1

Synthesis via Wittig reaction of 2-phenylbenzofuran derivatives 1–16(A) and 2-benzylbenzofuran derivatives 1–16(B). Reagents and conditions: (A) (a) NaBH₄, EtOH, 0 °C to rt, 2 h; (b) PPh₃ HBr, CH₃CN, 82 °C, 2 h; (B) (c) toluene, Et₃N, 110 °C, 2 h; (d) HI/AcOH/Ac₂O, 0 °C to reflux, 4 h.

Figure 1

Protein-ligand interaction picture. (A) The binding site of compounds 9A and 9B; and in (B) for compounds 10A and 10B. The key interacting residues are shown in ball-and-stick representation.