Benzodioxol Group Driving Supramolecular Arrangement of Two Tri-Methoxy Chalcones onto Β-Secretase 1 Enzyme Active Site

Vitor Duarte,Guilherme Oliveira,Nádia Borges,Jean Custodio,Hamilton Napolitano,Murilo Dos Anjos

doi:10.21577/0103-5053.20190101

Abstract

Chalcones are compounds with wide interesting biological activities including Alzheimer’s disease. A comparative study was performed between the chalcones (E)-1-(2-aminophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one and 1-(6-amino-1,3-benzodioxol-5-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one regarding the influence of benzodioxol group on their molecular conformations. The first chalcone was neutralized with dilute hydrochloric acid, while solid of the second was filtered and recrystallized from ethanol, both on centrosymmetric space group P21/c. Their molecular packing were evaluated by Hirshfeld surfaces, and both frontier molecular orbitals and molecular electrostatic potential (MEP) map were carried out by density functional theory (DFT) calculations. The compounds are stabilized by C–H…O and C–H…p interactions, as observed on MEP map, while the HOMO-LUMO gap indicated the conformational stability. The pharmacophore mapping approach was carried out for the identification of potential target candidates and then, further molecular docking analysis targeting the beta-secretase 1 (BACE-1) protein as a tactic to develop potential AD inhibitors, was performed. The AutoDock Vina score in redocking result for 2OHQ is –7.4 and –7.6 kcal moL-1. Additionally, the docking results for compounds inside the active site of the 2OHQ structure showed that both compounds bound to the BACE-1 active site with AutoDock Vina score of –6.0 kcal moL-1.

Highlights

We report a comparative analysis between chalcones ((E)-1-(2-aminophenyl)3‐(3,4,5‐trimethoxyphenyl)prop-2-en-1-one), C18H19NO4, (I) and (1-(6-amino-1,3-benzodioxol-5-yl)3‐(3,4,5‐trimethoxyphenyl)prop-2-en-1-one), C19H19NO6, (II).[22]
The active site of the enzyme was defined within two different grid size 12.45 × 12.69 × 13.70 Å and 20 × 20 × 20 Å centred at the geometric point (70.32, 47.34, 5.34 Å) on co-crystallized ligand
Except for the N–H···π interaction for I, the crystalline state of both chalcones is stabilized by C–H···O and C–H···π interactions, which were confirmed by the Hirshfeld surfaces

Summary

Introduction

Chalcones are chemical compounds often obtained in various types of plants or synthetic sources,[1,2,3] usually derived from the condensation of aromatic aldehyde with acetophenones in the presence of catalyst, being the principal precursors for the biosynthesis of flavonoids and isoflavonoids.[1,2,4] Basically, their structures are formed by two aromatic rings bounded by an open chain formed by an olefin portion and an α,β-unsaturated carbonyl system.[4,5] This compound class has attracted interest due to broad biological activities, such as anti-inflammatory, anti-fungal, anti-cancer, antibacterial, antiprotozal, anti-consulvant, anti-oxidant, anti-malarial, cytotoxic, insecticidal and treatment of Alzheimer’s disease.[6,7,8,9,10,11,12]Since many biological activities are attributed to chalcones, the understanding on how substituents affect theirVol 30, No 9, 2019In this article, we report a comparative analysis between chalcones ((E)-1-(2-aminophenyl)3‐(3,4,5‐trimethoxyphenyl)prop-2-en-1-one), C18H19NO4, (I) and (1-(6-amino-1,3-benzodioxol-5-yl)3‐(3,4,5‐trimethoxyphenyl)prop-2-en-1-one), C19H19NO6, (II).[22]. The frontier molecular orbitals (highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO)) is often associated with the electron donating ability of a molecule.[37] The energy of these orbitals can be calculated and are associated with the chemical stability index and the difference between them (gap) is related to the chemical reactivity, being described as to the minimum energy needed to excite an electron in the molecule.[38] The MEP presents the charge distribution of molecules three-dimensionally, and can determine regions of higher and lower electron densities of the molecule, contributing to interpret electrophilic and nucleophilic processes.[39,40] For the two compounds shown, this mapping contributes to the comparison of the reactive sites in the presence of the benzodioxol group.

Results

Conclusion