Mannich reaction derived novel boron complexes with amine-bis(phenolate) ligands: Synthesis, spectroscopy and in vitro/in silico biological studies

Highlights

• The new amine-bis(phenolate) boron complexes were prepared and fully characterized.

• The various spectroscopic methods were used for characterization of compounds

• The synthesized compounds were indicated great inhibition profile against the AChE with K_I values in the range from 5.48 ± 0.65 to 40.56 ± 4.42 µM

• The compounds showed about 18-45% DPPH and 26-85% ABTS radical scavenging activity.

• Molecular docking studies were carried out for the amine-bis(phenolate) ligands and their boron complexes.

Abstract

The amine-bis(phenolate) ligands was prepared through a Mannich reaction utilizing two equivalents of 2,4-di-tert-butylphenol or 4-tert-butylphenol, two equivalents of formaldehyde and a single equivalent of 2-aminoethyl diphenylborinate as primary amine. This work deals with the synthesis and evaluation of new (B←N) and (B-O) units containing amine-bis(phenolate) boron complexes designed by combination of amine-bis(phenolate) ligands and various boronic acids in toluene reflux using a Dean-Stark apparatus to remove water formed as a by-product. The newly synthesized amine-bis(phenolate) ligands and their boron complexes were characterized using elemental analysis, and their probable structures were proposed based on ¹H and ¹³C NMR, FT-IR, UV-Vis spectroscopy and LC-MS/MS spectrometry. The inhibition effects of the synthesized compounds on acetylcholinesterase (AChE) activity in vitro and their radical scavenging activities were evaluated. The AChE was effectively inhibited by compounds, with K_I values in the range from 5.48 ± 0.65 to 40.56 ± 4.42 µM. The (L₁B₄) has more inhibition effect on AChE with K_I value (6.37 ± 1.50 µM) in (L₂) series, while (L₂B₄) has an inhibition effect with K_I (5.48 ± 0.65 µM) in (L₂) series. Also, the compounds showed about 18-45% DPPH and 26-85% ABTS radical scavenging activity. On the other hand, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT) and Trolox showed about 72-96% DPPH and 94-96% ABTS radical scavenging activity, respectively in the same concentration (25-30 µg/mL). Besides, the (L₁B₄), (L₁B₅), and (L₂B₄) determined as the most active inhibitors were docked into the binding site of AChE to find the binding interactions of the boron complexes with the protein.

Introduction

Boron-based organic synthesis, such as amine-bis(phenolate) boron complexes wherein the boron is coordinated to an organic amine-bis(phenolate) ligand, maybe become one of the most popular research areas due to their interesting properties and unique coordination chemistry of boron which allows preparation of multifunctional novel organic compounds. Because they offer potential advantages such as unique electronic and photo physical properties, enhanced flexibility and solution process ability at low cost, boron complexes continue to attract great interest in applications ranging from Lewis-acidic character [1] to pharmaceutical industry [2], [3], [4], catalysis [5], [6], [7], [8] and biological imaging [9] etc. However, this area is still in its infancy and the design and preparation of different boron complexes are challenging tasks. This is mostly due to the labile nature of ligands attached to the tetra-coordinated boron atom that makes it configurationally unstable. Accordingly, the choice of the nature of boron's ligands is crucial [10]. Also, the recent time interest for tetra-coordinated boron complexes comes from the fact that they are easily available, stable and, more importantly, are quite resistant to dissociation compared with tri-coordinate boron compounds [11], [12], [13]. Therefore, we think that choosing amine-bis (phenolate) groups as ligand will remove some restrictions in the boron area and will be important research topics.

The use of chelating tetra dentate amine-bis(phenolate) ligands have recently played an increasingly important role in transition-metal catalyst design and modelling of metalloenzyme active-sites. During several years we have studied the different behavior exhibited by these ligands, mainly due to the potential reduction capacity showed by the chemical group which leads to a great variety of coordination patterns [14]. Other than these, amine-bis(phenolate) ligands which is a chelating tetra dentate has been an attractive subject in combination with various metals such as Fe, Co, Rh, Zr, and Cr and these metal complexes have been acted as catalysts for cross-coupling of alkyl halides [15], [16], [17], [18], [19], 1-hexene polymerization [20], hydrogenation of ketones [17] and CO₂ conversion [21]. To the best of our knowledge, the synthesis and applications in different fields of amine-bis(phenolate) boron complexes are very rare. In this context, we think that amine-bis(phenolate) boron complexes coordinated with various boronic acids will be used in many new application areas today and will be an important new class of boron compounds.

Boronic acids are a class of compounds that have received considerably more attention in recent years because of the unique reactivity they confer upon complexation with diols [22]. A boronic acid is a trivalent boron-containing compound that has two hydroxyls and one alkyl or aryl functional groups. The functional group bonded to boron determines the reactivity of boronic acid [23,24]. Differently in this study, we preferred amine-bis(phenolate) ligands instead of diols for coordinated with boronic acids. Additionally, these new boron compounds are 1:1 Lewis type intramolecular noncovalent B←N coordination bonds formed from boronic esters and amine-bis(phenolate) ligands, of which the former are derived from arylboronic acids and catechol derivatives.

Molecular oxygen, one of the main sources of free radicals, is a stable radical, it is also a necessary compound for life and cell function. Cells produce oxygen-centered radicals with various physiological processes. Reactive oxygen species (ROS) are among the most important of these endogenously occurring species [25]. Free radicals having a single unpaired electron in their outer orbitals have a very reactive property [26,27]. When produced in foods or biological tissues, these species, which are generally harmful to humans, react easily with macromolecules such as lipids, carbohydrates, protein and nucleic acids, producing different radical and non-radical species [25,28]. The radicals, which cause lipid peroxidation, DNA damage and protein oxidation, are known to play an important role in the formation of many neurodegenerative diseases such as Alzheimer's disease [29,30]. It has been reported that ß-amyloid, which is associated with Alzheimer's disease, also produces free radicals. ß-amyloid interacts with vascular endothelial cells, producing superoxide radicals and oxidizing agents that cause lipid peroxidation. This suggests that ß-amyloid plays a role in the production of free radicals and the formation of Alzheimer's disease [31]. There is a significant relationship between the increase of beta amyloids and the acetylcholinesterase (AChE), which hydrolyzes the neurotransmitter acetylcholine involved in cholinergic metabolism [32]. In previous studies, it has been reported that ß-amyloid increases with increasing AChE activity. This shows that AChE can indirectly contribute to the formation of free radicals. Therefore, the synthesis of new compounds with both radical scavenging and AChE inhibitory properties is important.

Continuing this research, our groups are interested in all aspects of boron chemistry, including the synthesis, characterization, catalysis and pharmaceutical chemistry of different organic ligands for boron coordination. In this paper, we present the formation of newly synthesized amine-bis(phenolate) ligands (L₁ and L₂) and their four-coordinated boron complexes [L₁B_(1-5)] and [L₂B_(1-5)] for in silico and in vitro biological evaluation. For this purpose, the inhibition effects of the synthesized compounds on AChE activity and their radical scavenging activities were scanned.