Elsevier

Bioorganic Chemistry

Volume 87, June 2019, Pages 91-102
Bioorganic Chemistry

Synthesis and characterization of novel bromophenols: Determination of their anticholinergic, antidiabetic and antioxidant activities

https://doi.org/10.1016/j.bioorg.2019.03.010Get rights and content

Highlight

  • A series of novel bromophenol derivatives were synthesized.

  • Their acetylcholinesterase and α-glycosidase inhibition effects was investigated.

  • DPPHradical dot and ABTS⋅+ scavenging effects of bromophenol were evaluated.

  • Fe3+ and Cu2+ reducing and Fe2+ chelating of bromophenols were determined.

  • Antioxidant and enzyme inhibition effects of bromophenols were compared to the standards.

Abstract

In this paper, a series of novel bromophenol derivatives were synthesized and evaluated for their acetylcholinesterase and α-glycosidase enzymes inhibition properties and antioxidant activity. Diarylmethanones were synthesized and their bromination was carried out. During bromination, some compounds gave new bromophenols via regioselective O-demethylation. Demethylation of brominated diarylmethanones was also performed with BBr3 to give novel bromophenols. In addition, we examines the antioxidant capacity of novel bromophenol derivatives using several in vitro bioanalytical methodologies such as 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS⋅+) and 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPHradical dot) radical scavenging activity, Fe3+ and Cu2+ reducing activities and ferrous (Fe2+) ions chelating activities. Also, novel bromophenols and methoxylated bromophenols derivatives were tested against acetylcholinesterase and α-glycosidase, which associated with some metabolic diseases. The novel bromophenols showed Ki values in range of 8.94 ± 0.73–59.45 ± 14.97 nM against AChE and 4.31 ± 1.93–44.14 ± 2.19 nM against α-glycosidase.

Graphical abstract

A series of novel bromophenol derivatives were synthesized and evaluated for their antioxidant activity, α-glycosidase and acetylcholinesterase enzymes inhibition properties. The most powerful inhibition was observed from (2,3-Dibromo-4-hydroxy-5-methoxyphenyl)(2,5-dibromo-4-methoxyphenyl)methanone as 4.31 ± 1.93 nM α-glycosidase enzyme, which promise as antidiabetic agent. This compound can be researched in further studies related diabetes mellitus as lead compound.

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Introduction

Natural products are playing important role in design and the development of new drugs. Natural products and their semi-synthetic derivatives are important source of medicine and there are a large number of natural compounds used as drugs today [1]. Bromophenols, secondary metabolites of marine organisms, are also natural organic compounds [2]. Most of these compounds are generally isolated from marine red algae [3], brown algae [4], and green algae [5]. Compounds 15 are examples of naturally occurring bromophenols and they show various biological activities such as radical scavenging [6], antibacterial [3], anti-cancer [7], feeding deterrent [8], antidiabetic [9], aldose reductase inhibition [10], and tyrosine phosphatase properties [11] (Fig. 1).

Because of the diverse biological activities of bromophenols, in the last decade, our research group has also focused on the total synthesis of naturally occurring bromophenols and their synthetic derivatives. In these studies we reported an alternative synthesis of 1 [12] and the first total synthesis of 25 [13], [14], [15]. Together with the natural products, some phenolic brominated benzophenones were also synthesized. We well know from our early studies that diarylmethanones are also potent enzyme inhibitors as natural bromophenol derivatives. The acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carbonic anhydrase inhibitory properties of 69 were reported in this journal [15] (Fig. 1). In addition, antioxidant activity [12], AChE [16], paraoxonase [17], aldose reductase, α-amylase and α-glycosidase [18] inhibitory properties of some bromophenols have been addressed by our research group. In continuation of our studies, here we report the synthesis, antioxidant activity, acetylcholinesterase and α-glycosidase inhibition properties of some novel bromophenols incorporating diarylmethanone skeleton.

Oxidation is an essential biological process to many living organisms a result of normal cellular metabolism for the production of energy [19], [20]. Reactive oxygen species (ROS) can occur in the human body and have a strong effect of inducing lipid peroxidation (LP), which in turn induces oxidative imbalance and causes various diseases. LP is a major deteriorative process in pharmaceuticals and foods. ROS can cause a myriad of diseases such as ageing, cardiovascular ailments, cancer and deficiencies of immune system [21], [22], [23]. They are easily formed in the living metabolism and neutralized by antioxidant defenses. Also, excessive amount of ROS can damage cellular components including DNA, membrane lipids, proteins and monosaccharides, inducing many diseases including aging and cancer atherosclerosis, pulmonary dysfunction, skin lesions and inflammatory disorders [24], [25], [26]. On the other hand, antioxidants can block formation of ROS and free radical reactions by donating an electron or a hydrogen atom to reactive species and free radicals [27]. Antioxidants can retard the production of toxic oxidation compound, and increase the shelf life of food products [28], [29]. The phenolic compounds are one of the most abundant secondary metabolites and well-studied antioxidants in vitro and in vivo [30], [31], [32]. They are major groups of secondary metabolites, and their biosynthetic precursors are metabolites of the shikimate, pentose phosphate and phenylpropanoid pathways [33]. Thus, there was a need to identify the alternative and safer antioxidants. Recently, these demands have increased significantly [34].

Alzheimer’s disease (AD) affects mostly the aged people and above resulting in impaired memory and behavior. This disorder clinically involves the progressive degeneration of brain tissue that is influenced by the deficit in acetylcholine (ACh) [35], [36], [37]. AChE, a major element of the cholinergic system in the peripheral and central nervous system (CNS), is able to convert acetylcholine (ACh) to acetate and choline (Ch) [38], [39], [40]. It is caused majorly by environmental and genetic influences. Cerebral amyloid-β aggregation, a deficit in ACh and a deficit in cholinergic neurotransmission, was observed in patients with AD [41], [42], [43]. Because of serious side effects of the available AChE, there is the need to search for newer effective and safe AChE to treat neurodegenerative damages. AChE inhibitors (AChEIs) or anti-cholinesterases inhibit cholinesterase, increasing the level and length of ACh action. A variety of usages of AChEIs are common in medicine. As a result, a number of AChEIs have been thought for the treatment of AD. They have been used in clinical trials, including natural substances. It was reported that terpenoids, flavonoids and phenolic compounds have been recognized as AChEIs and promising lead compounds for AD [41], [44].

α-Glycosidase enzyme (E.C.3.2.1.20) release from intestine cells and hydrolyzes oligosaccharides and polysaccharide to monosaccharide units, such as glucose and fructose in small intestine. In human, α-glycosidase inhibitors (α-GIs) had a great importance for controlling of type-2 diabetes (T2DM) and hyperglycemia [45]. Recently, two main chemical classes of N-comprising α-GIs contain carbasugar-based inhibitors like acarbose and voglibose and iminosugar-based inhibitors like miglitol have been developed [46]. α-GIs can reduce the uptake of dietary carbohydrates and repress postprandial hyperglycemia and T2DM. Thus, these α-GIs are endowed with sugar molecule such as compete and moieties with the oligosaccharides for binding to the active site of the enzyme, hence effectively reducing the postprandial glucose amounts in T2DM [47]. On the other hand, bromophenols as natural compounds are secondary plant and marine organisms metabolites and consist of brominated and hydroxylated benzyl unit. There is a large number recent study on the synthesis, biological activities and isolation of bromophenols. Also, their antioxidant activities and AChE, BChE and hCA inhibitory effectiveness were well established [47], [48], [49].

In this regards, we synthesized novel bromophenols 16, 17, 20 and 21 and methoxylated bromophenols derivatives 12, 18 and 19. We also verified the antioxidant activities of the resultant compounds using fife different bioanalytical methods, namely, ferrous ions (Fe2+) chelating, cupric ions (Cu2+) and ferric ions (Fe3+) reducing antioxidant power, 1,1- diphenyl-2-picrylhydrazyl (DPPHradical dot) and the 2,2′-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS+) radicals scavenging assays. These novel compounds were tested against acetylcholinesterase, and α-glycosidase as crucial metabolic enzymes either. Furthermore, another goal of this study is to demonstrate antioxidant activities of novel bromophenols and methoxylated bromophenols derivatives as compared to putative commercial and standard compounds.

Section snippets

Chemistry

Benzene derivatives are easily giving acylation reaction with benzoic acid derivatives in the presence of polyphosphoric acid (PPA) [15]. The synthesis of diarylmethanone 12 was accomplished by a similar approach. Therefore, the reaction of 2-bromoanisole (11) with 3,4-dimethoxybenzoic acid (10) in the presence of PPA newly prepared from conc. H3PO4 and P2O5 gave compound 12 in a moderate yield (Scheme 1). Compounds 1315 were synthesized as described above and as reported in a previous paper

Conclusion

In conclusion, diarylmethanone 12 was synthesized for the first time. The bromination of 12 and the known diarylmethanones 1315 were investigated in this study. Interestingly regioselective O-demethylation was observed during bromination of compounds 12 and 13. The structures of brominated products 1619 were characterized. The synthesized compounds 12 and 1621 were evaluated for their biological assays like antioxidant activity, AChE and α-glycosidase inhibition properties. Novel

General

All chemicals and solvents are commercially available. All solvents were distilled and dried as describes in the standard procedures. Silica gel (SiO2, 60 mesh) was used for column chromatography. A total of 1 mm of SiO2 60 PF on glass plates was used for preparative thick layer chromatography. Melting point of all compounds was determined with capillary melting-point apparatus (BUCHI 530), which are uncorrected. IR spectra were recorded as solutions in 0.1 mm cells with a Mattson 1000 FT-IR.

Acknowledgments

The authors are indebted to Ataturk University for financial support of this work (Project No: FBA-2017-6124).

Declaration of interest

The authors report no conflicts of interests.

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