Molecular Docking Studies of Coumarin Hybrids As Potential Acetylcholinesterase, Butyrylcholinesterase, Monoamine Oxidase A/B An
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Yusufzai et al. Chemistry Central Journal (2018) 12:128 https://doi.org/10.1186/s13065-018-0497-z Chemistry Central Journal REVIEW Open Access Molecular docking studies of coumarin hybrids as potential acetylcholinesterase, butyrylcholinesterase, monoamine oxidase A/B and β‑amyloid inhibitors for Alzheimer’s disease Samina Khan Yusufzai1, Mohammad Shaheen Khan2*, Othman Sulaiman1, Hasnah Osman3 and Dalily Nabilah Lamjin2 Abstract Coumarins are the phytochemicals, which belong to the family of benzopyrone, that display interesting pharmaco- logical properties. Several natural, synthetic and semisynthetic coumarin derivatives have been discovered in decades for their applicability as lead structures as drugs. Coumarin based conjugates have been described as potential AChE, BuChE, MAO and β-amyloid inhibitors. Therefore, the objective of this review is to focus on the construction of these pharmacologically important coumarin analogues with anti-Alzheimer’s activities, highlight their docking studies and structure–activity relationships based on their substitution pattern with respect to the selected positions on the chromen ring by emphasising on the research reports conducted in between year 1968 to 2017. Keywords: Coumarin, Neurodegenerative disorder, Alzheimer’s disease, Acetylcholinesterase, Butyrylcholinesterase, Monoamine oxidase Introduction production and clearance of Aβ peptide and thus Aβ Alzheimer’s disease (AD) is the most common form forms highly insoluble and proteolysis resistant fbrils of neurodegenerative disorder and the most prevalent known as senile plaques (Fig. 1) [1]. Tese plaques will cause of dementia commonly afecting the elderly. It is a interrupt the neuron transmission at synapses and cause progressive disorder of the brain that is associated with information transfer to fail leading to the neuronal cell the loss of presynaptic markers of the cholinergic sys- death. NFTs are composed of the tau amyloid protein tem in the brain, which is related to memory and ability fbrils (Fig. 2) [2]. to carry out daily activities. It is said to be progressive Tau is a component of microtubules that provides the as its symptoms worsen over time. Two main causes of internal support structure for the transport of nutri- AD are plaques and neurofbrillary tangles (NFTs) which ents and essential molecules within the cell. When tau results due to the accumulation of beta-amyloid protein is hyperphosphorylated, it forms insoluble fbrils that (Aβ) outside the neurons. Aβ is formed by the proteo- blocks the transport of nutrients and essential molecules lytic cleavage of amyloid precursor protein (APP) which in the neuron thus leading to cell death [3]. Jack et al. occurs by α-secretase and is aberrantly processed by proposed a hypothetical model which explains about the β- and γ- secretases resulting in an imbalance between progression of AD and how pathological events such as deposition of Aβ fbrils and increased levels of tau protein in cerebrospinal fuid (CSF), lead to cognitive impairment *Correspondence: [email protected] and dementia (Fig. 3) [4]. To date, the cure of this disease 2 Industrial Chemistry Programme, Faculty of Science and Natural Resources, Universiti Malaysia Sabah, 88400 Kota Kinabalu, Sabah, is yet to discover. Nonetheless, researchers have found Malaysia various alternatives to slow down its progression. Among Full list of author information is available at the end of the article these alternatives are, inhibition of acetylcholinesterase © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yusufzai et al. Chemistry Central Journal (2018) 12:128 Page 2 of 57 Fig. 1 Diagrammatic presentation of APP processing pathways [1] Fig. 2 Generation of soluble Aβ fbrils from amyloid precursor protein [2] Yusufzai et al. Chemistry Central Journal (2018) 12:128 Page 3 of 57 Fig. 3 Hypothetical model for biomarker dynamics in the progression of Alzheimer’s disease [4] (AChE), APP, β-secretase, γ-secretase, monoamine oxi- improve the learning and memory defcits in the animal dase (MAO) and metal chelators [5]. models, associated with AD and to slow the disease pro- Te frst line treatment that is given to AD patients is gression in AD patients [11–13]. Zatta et al. reported that AChE inhibitors because not only they facilitate cholin- dyshomeostasis and miscompartmentalization of metal ergic transmission, they also interfere with the synthe- ions such as Fe2+, Cu2+ and Zn2+ occurs in the brain sis, deposition and aggregation of toxic Aβ. Tis might of AD patients. Te formation of Aβ plaques, neurof- lead to the improvement of cognition and some behav- brillary tangle as well as production of reactive oxygen ioural problems [6–8]. Te enzyme butyrylcholinest- species (ROS) and oxidative stress are closely linked to erase (BuChE) has the same role as AChE, which is to the highly concentrated metal ions in the neuropil and hydrolyse the acetylcholine in the synaptic cleft. How- plaques of the brain [14]. Modulation of such biometals ever, their inhibition might help in enhancing the ef- in the brain represents an additional rational approach ciency of treatment for the AD patients. Xie et al. stated for the treatment of AD [12, 14]. Another approach that that even though the activity of AChE decreases as the gained interest among the researchers was to lower the disease progresses, the activity of BuChE shows a sig- Aβ level by inhibiting the β-secretase (BACE1), which is a nifcant increase in the hippocampus and temporal cor- transmembrane aspartyl protease, responsible for N-ter- tex. BuChE inhibitors might help to improve cholinergic minal cleavage of the APP which leads to the production activity by restoring the AChE/BuChE activity ratios as of Aβ peptide [15]. seen in the healthy brain [9]. Recent investigations are Coumarin and its derivatives are reported to display focusing more on dual AChE/BuChE inhibitors [8–10]. wide range of biological activities such as anti-diabetic Monoamine oxidase B (MAO-B) is an important factor and antidepressant [16], anti-oxidant [17], anti-cancer that is involved in oxidative stress and oxidative stress [18], anti-proliferative [19], antinociceptive [20], anti- is said to be among the multiple factors, which induce bacterial and anti-tubercular [21], hepatoprotective, the AD. It is widely established in the literature that the anti-allergic, anti-HIV-1, antiviral, antifungal, antimicro- activity of MAO-B can increase up to threefold in the bial and antiasthmatic [22]. Te benzopyrone moiety of temporal, parietal and frontal cortex of AD patients as the coumarin nucleus is known as the fundamental for compared to the controls. Tis increase in MAO-B activ- the design of hybrid molecule that can simultaneously ity produces higher levels of H 2O2 and oxidative free rad- inhibit AChE and AChE induced β-amyloid accumula- icals, which has been correlated, with the development tion. Studies have also shown that naturally occurring as of Aβ plaques. MAO-B inhibitors, hold the potential to well synthetic coumarin analogues exhibit potent AChE, be developed into efective anti-Alzheimer’s drugs, as it BuChE, dual AChE/BuChE and MAO inhibitory activity has been reported before, that MAO-B inhibitors such [12, 23–25]. Coumarin’s versatility allows chemical sub- as selegiline and rasagiline has shown to signifcantly stitutions to occur at diferent sites in its structure, thus Yusufzai et al. Chemistry Central Journal (2018) 12:128 Page 4 of 57 N O O Fig. 4 Molecular structure of coumarin 106 or C1 making it a compelling molecule for drug discovery [7, 8]. Modifcation of coumarin ring to develop new analogues of coumarin with superior activity is the main focus of the current review which is based on the reports which were taken in between the year 1968–2017. Coumarin analogues as AChE inhibitors Fallarero et al. [7] reported an active AChE inhibitor among a coumarin library consisting of 29 coumarins, including coumarin itself and several derivatives of the 7-hydroxy and 7-methoxy-coumarin as well as seven synthetic coumarins. Te molecule that showed most active AChE inhibitory activity is C1, chemically known as 2,3,5,6,7,9,10,11-octahydrocyclopenta[4,5]pyrano[2,3- f]pyrido[3,2,1-ij]quinolin-12(1H)-one or coumarin 106 (Fig. 4). In order to recognize how this compound act as AChE inhibitor and interacts with the target, Fallarero et al. [7] docked C1 into the enzyme AChE and predicted its binding mode. Te result that was obtained showed that C1 was able to penetrate into the enzyme’s active site gorge and bind to the AChE peripheral anionic site (PAS) as a secondary binding site (Fig. 5). It was reported before that binding to the PAS of the AChE might decrease the accumulating efects of the enzyme on the β-amyloid peptide, and hence the ability of C1 Fig. 5 a Propose binding of C1 at the active gorge site. b Propose binding of C1 at the peripheral anionic site [7] to bind to the peripheral anionic site of AChE proves its potential as drug lead or molecular probe for the AD treatment [7]. Razavi et al. designed and synthesized a series of this activity was further justifed by the help of docking 4-hydroxycoumarin derivatives [27]. Tey screened study of C3. Te best docking pose of C3 and amino them towards electrophorus electricus acetylcho- acids in the active site of Torpedo californica acetylcho- linesterase (eelAChE) and horse serum butyryl- linesterase (TcAChE) is represented in Fig.