Design, synthesis and biological evaluation of benzofuran appended benzothiazepine derivatives as inhibitors of butyrylcholinesterase and antimicrobial agents
Graphical abstract
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)
- et al.
Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine
Neurosci
(2002) - et al.
1,5-Benzothiazepine, a versatile pharmacophore: A review
Eur J Med Chem
(2008) - et al.
Effects of a novel, potent benzothiazepine Ca2+ channel antagonist, DTZ323, on guinea-pig ventricular myocytes
Eur J Pharmacol
(1997) - et al.
Solid-phase synthesis and biological evaluation of a parallel library of 2,3-dihydro-1,5-benzothiazepines
Bioorg Med Chem
(2008) - et al.
Synthesis, characterization, biological evaluation and QSAR studies of 11-p-substituted phenyl-12-phenyl-11a,12-dihydro-11H-indeno[2,1-c][1,5]benzothiazepines as potential antimicrobial agents
Eur J Med Chem
(2012) - et al.
Synthesis and biological evaluation of a novel series of 1,5-benzothiazepine derivatives as potential antimicrobial agents
Eur J Med Chem
(2009) - et al.
Design, synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase inhibitors
Bioorg Med Chem Lett
(2017) - et al.
Design, synthesis, and antiviral activities of 1,5-benzothiazepine derivatives containing pyridine moiety
Eur J Med Chem
(2017) - et al.
Efficient synthesis of 3H,3′H-spiro[benzofuran-2,1′-isobenzofuran]-3,3′-dione as novel skeletons specifically for influenza virus type B inhibition
Eur J Med Chem
(2013) - et al.
Synthesis and antimicrobial evaluation of new benzofuran derivatives
Eur J Med Chem
(2011)