Design, synthesis and biological evaluation of benzofuran appended benzothiazepine derivatives as inhibitors of butyrylcholinesterase and antimicrobial agents

This article is dedicated to Prof. Dr. Abbas Shafiee who recently passed away.
https://doi.org/10.1016/j.bmc.2018.02.049Get rights and content

Abstract

A series of bezofuran appended 1,5-benzothiazepine compounds 7a–v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC50 value ranging between 1.0 ± 0.01 and 72 ± 2.8 μM when compared with the standard donepezil (IC50, 2.63 ± 0.28 μM). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC50 values of 1.0, 1.0 and 1.8 μM, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.

Introduction

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two important types of cholinesterase species. They are mainly responsible for the hydrolysis of acetylcholine (ACh) into choline and acetic acid which is an essential process allowing for the control of the cholinergic transmission.1 Low levels of ACh is a key pathological hallmark of Alzheimer’s disease (AD).2 AD is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory.3, 4 In a healthy brain, ACh is predominantly (80%) hydrolyzed by AChE, whereas BChE plays a supplementary role. However, with progression of AD, the AChE activity decreases, whereas the activity of BChE gradually increases.5, 6 This phenomenon enhances the significance of BChE as an additional therapeutic target for reducing the cholinergic deficiency inherent in AD.7, 8 Currently, AD therapy is mainly founded on cholinesterase inhibitors, which are able to increase ACh levels in cholinergic synapses.9 Recent studies have demonstrated that BChE inhibition results in improved cognitive potential with elevated levels of ACh in brain and hence, it may act as an effective therapeutic strategy for AD.10, 11, 12, 13

1,5-Benzothiazeoines are considered privileged scaffolds in drug discovery for cardiovascular and neurodegenerative diseases. 1,5-Benzothiazepine derivatives have a broad spectrum of therapeutic applications as coronary vasodilator,14 Ca+2 channel antagonists,15 antidepressant,16, 14 acetylcholinesterase inhibitors,17 butyrylcholinesterase inhibitors,18 and antimicrobial agents.19, 20, 21 Benzofurans, a groups of naturally occurring substances in many plants, exhibit a wide range of biological activities.22, 23 Benzofuran scaffold has emerged as an important pharmacophore for designing antiviral24, 25 and antimicrobial agents26, 27 and inhibitors of cyclin-dependent kinases (CDKs)28 and cholinesterase.29, 30 Combination of 1,5-benzothiazepine and benzofuran moiety exhibited synergistic effect thereby, enhancing their potency.

In the light of above-mentioned findings, and as a continuation of our endeavor to identify new candidates that might be advantageous in designing new, potent, selective, and less toxic cholinesterase inhibitors,31, 32, 33, 34 we have reported the synthesis of 1,5-benzothiazepine derivatives containing benzofuran fragments at C-4 position. All synthesized compounds were screened for their ability to inhibit the enzyme activities of BChE and their in vitro antimicrobial activity. To better understand the enzyme inhibition mechanisms, in relation to the substituents and their positions in the presented compounds, molecular modeling studies were also performed.

Section snippets

Chemistry

The synthesis of 1,5-benzothiazepine derivatives 7a–v was outlined in Scheme 1. First, 2-acetylbenzofuranes 3a–d were prepared from the ring closure reaction of salicylaldehyde derivatives 1a–d and chloroacetone 2 (Table 1). Then, condensation of 2-acetylbenzofuranes 3a–d with various benzaldehydes 4a–k under microwave irradiation in the presence of catalytic amount of piperidine gave α,β-unsaturated carbonyl compounds 5a–v (Table 2). Finally, the thia Michael addition and further

Conclusion

In summary, twenty-two substituted 1,5-benzothiazepine derivatives bearing benzofuran moiety have been synthesized and fully characterized. The synthetic pathway was quick and effective. All compounds were evaluated in vitro for their ability to inhibit AChE and BChE and the resulting products showed good levels of inhibition against BChE. In particular, compounds 7l, 7m, and 7k expressed the highest BChE-inhibiting activities. Kinetic analysis studies revealed that compound 7l features a

General information

All commercially available reagents were purchased from Merck AG, Aldrich or Acros Organics and used without further purification. Column chromatography was carried out on silica gel (70–230 mesh). TLC was conducted on silica gel 250 µm, F254 plates. For the synthesis of compounds 7 the experiments were performed using a microwave oven (ETHOS 1600, Milestone) with a power of 300 W specially designed for an organic synthesis and modified with a condenser and mechanical stirrer. Melting points

Acknowledgements

The authors are thankful for the financial support from the Research Council of Alzahra University and the Research Council of Tehran University of Medical Sciences and Iran National Science Foundation (INSF). N. L. thanks the National Elites Foundation of Iran, Tehran (BMN) for support of this work.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This work was prepared under the supervision of Prof. Abbas Shafiee who

References (49)

  • C. Kirilmis et al.

    Synthesis and antimicrobial activity of some novel derivatives of benzofuran: Part 2. The synthesis and antimicrobial activity of some novel 1-(1-benzofuran-2-yl)-2-mesitylethanone derivatives

    Eur J Med Chem

    (2008)
  • J. Wu et al.

    Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: Binding mode, inhibitory mechanism and biological action

    Eur J Med Chem

    (2013)
  • Y. Xiang et al.

    The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors

    Bioorg Med Chem Lett

    (2011)
  • M. Mostofi et al.

    Synthesis and structure-activity relationship study of benzofuran-based chalconoids bearing benzylpyridinium moiety as potent acetylcholinesterase inhibitors

    Eur J Med Chem

    (2015)
  • M. Alipour et al.

    Novel coumarin derivatives bearing N-benzyl pyridinium moiety: potent and dual binding site acetylcholinesterase inhibitors

    Bioorg Med Chem

    (2012)
  • M. Khoobi et al.

    Design, Synthesis, Biological Evaluation and Docking Study of 5-Oxo-4,5-Dihydropyrano[3,2-C]chromene Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors Eur

    J Med Chem

    (2013)
  • C. Paizs et al.

    Optically active 1-(benzofuran-2-yl)ethanols and ethane-1,2-diols by enantiotopic selective bioreductions

    Tetrahedron Asymmetry

    (2003)
  • K. Manna et al.

    Microwave assisted synthesis of new indophenazine 1,3,5-trisubstruted pyrazoline derivatives of benzofuran and their antimicrobial activity

    Bioorg Med Chem Lett

    (2009)
  • K. Manna et al.

    Design, synthesis, and antitubercular evaluation of novel series of 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin analogs

    Eur J Med Chem

    (2010)
  • G.L. Ellman et al.

    A new and rapid colorimetric determination of acetylcholinesterase activity

    Biochem Pharmacol

    (1961)
  • G.L. Delogu et al.

    2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling

    Bioorg Med Chem Lett

    (2016)
  • A. Samadi et al.

    Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: New dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease

    Eur J Med Chem

    (2013)
  • M.B. Colovic et al.

    Acetylcholinesterase inhibitors: pharmacology and toxicology

    Curr Neuropharmacol

    (2013)
  • E.J. Mufson et al.

    Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications

    Expert Rev Neurother

    (2008)
  • Cited by (0)

    View full text