Summary of organic chemistry doctoral thesis: Design, synthesis and evaluation of acetylcholinesterase inhibitory activity of chalcone derivatives for the discovery of new anti-alzheimer drugs

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The objectives of the thesis: Molecular docking studies on acetylcholinesterase were performed to predict the chalcone structure has good in silico AChE acetylcholinesterase inhibitory activity. The potential chalcone compounds were synthesized and studied for their in vitro and in vivo AChE inhibitory activities

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Nội dung Text: Summary of organic chemistry doctoral thesis: Design, synthesis and evaluation of acetylcholinesterase inhibitory activity of chalcone derivatives for the discovery of new anti-alzheimer drugs

MINISTRY OF EDUCATION VIETNAM ACADEMY OF AND TRAINING SCIENCE AND TECHNOLOGY GRADUATE UNIVERSITY SCIENCE AND TECHNOLOGY ----------------------------- TP Hồ Chí Minh - Năm 2017 Nguyen Thi Cam Vi DESIGN, SYNTHESIS AND EVALUATION OF ACETYLCHOLINESTERASE INHIBITORY ACTIVITY OF CHALCONE DERIVATIVES FOR THE DISCOVERY OF NEW ANTI-ALZHEIMER DRUGS Major: Organic chemistry Code: 9.44.01.14 SUMMARY OF ORGANIC CHEMISTRY DOCTORAL THESIS Ho Chi Minh – 2018
The doctoral thesis was finished at: Graduate University Science and Công trình được hoàn thành tại Viện Công Nghệ Hóa Học Technology - Vietnam Academy of Science and Technology. Viện Khoa Học và Công Nghệ Việt Nam Người The 1sthướng dẫnAssoc. supevisor: khoa học Prof. Dr. Tran Thanh Dao 1.The PGS. 2ndTS. TRẦN Assoc. supevisor: THÀNH ĐẠO Prof. Dr. Thai Khac Minh 2. PGS. TS. THÁI KHẮC MINH The 1st doctoral thesis reviewer: … Phản biện 1: TS. Nguyễn Thụy Việt Phương The 2nd doctoral thesis reviewer: … The 3rd doctoral thesis reviewer: …. Phản biện 2: GS. TS. Phan Thanh Sơn Nam The doctoral thesis will be protected at the evaluation coucil of PhD dissertation (Academy degree), meeted at Graduate University Science and Technology - Vietnam Academy of Science and Luận án sẽ được bảo vệ trước Hội đồng đánh giá luận án Technology, … Viện cấp cơ sở họpattại Công am (pm), … month dayNghệ Hóa…Học, 201…. yearViện Khoa Học và Công Nghệ Việt Nam. Vào hồi……….. giờ ………… ngày ………. tháng ………. năm 2017 Read Có thểthe doctoral tìm hiểu thesis: luận án tại: Viện Công Nghệ Hóa Học và Thư Viện quốc gia. - Graduate University Science and Technology Library - National Library of Vietnam
INTRODUCTION 1. The urgency of the thesis Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is affecting millions of people worldwide. The ailment is characterized by a complex neurodegenerative process occurring in the central nervous system which leads to progressive cognitive decline and memory loss. [1] The etiology of AD is not fully known, although factors including the low levels of acetylcholine (ACh), accumulation of abnormal proteins namely -amyloid and -protein, homeostasis irregularity of biometals, and oxidative stress are considered to play signiﬁcant roles in the pathophysiology of AD.[2] At the present , clinical therapy for AD patients is primarily established upon the cholinergic hypothesis which suggests that the decline of the ACh level might lead to cognitive and memory deﬁcits, and drugs with the ability of inhibiting acetylcholinesterase (AChE) would control symptoms of the disease.[1] Chalcone is a sub-group of flavonoid and is the intermediary in the synthesis process of other flavonoids, pyrazoline, isoxazole, and quinolinylpyrimidine. There are a lot of chalcone compounds which are reported to have a diverse array of bioactivities such as antibacterial, antifungal, antiviral, antioxidant, antitumoral, and other characteristics such as anti-inflammatory, analgesic, antiulce. Recent studies on the bioactivities of chalcone compounds have also revealed their abilities in inhibiting enzymes including urease, - glucosidase, lipoxygenase, acetylcholinesterase, mammalian alpha- amylase, xanthine oxidase58, monoamine oxidase (MAO), and - secretase. In addition, it was reported that chalcone derivatives exhibit high binding afﬁnity to A aggregates in vitro, and they 1
could serve as a useful mean for in vivo imaging of A plaques in Alzheimer’s brain.[2-4] The studies on bioactivities of chalcone derivatives on the function of human brain promise the finding of new drugs for the treatment of many diseases including AD. From the above scientific bases, the research project "Design, synthesis and acetylcholinesterase inhibitory activity evaluation of chalcone derivatives for the discovery of new anti-alzheimer drugs" was conducted. 2. The objectives of the thesis Molecular docking studies on acetylcholinesterase were performed to predict the chalcone structure has good in silico AChE acetylcholinesterase inhibitory activity. The potential chalcone compounds were synthesized and studied for their in vitro and in vivo AChE inhibitory activities. 3 . The main contents of the thesis - The molecular binding abilities of chalcone derivatives with ACHE were elucidated by docking procedure to predict the chalcone structure has good in silico AChE acetylcholinesterase inhibitory activity. - The potential chalcone compounds were synthesized and studied for their in vitro and in vivo AChE inhibitory activities. Chapter 1. OVERVIEW 1.1. Alzheimer disease Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is affecting millions of people worldwide. The ailment is characterized by a complex neurodegenerative process occurring 2
in the central nervous system which leads to progressive cognitive decline and memory loss. [1] The etiology of AD is not fully known, although factors including the low levels of acetylcholine, accumulation of abnormal proteins namely -amyloid and -protein, homeostasis irregularity of biometals, and oxidative stress are considered to play signiﬁcant roles in the pathophysiology of AD.[12] At the present , clinical therapy for AD patients is primarily established upon the cholinergic hypothesis which suggests that the decline of the ACh level might lead to cognitive and memory deﬁcits, and drugs with the ability of inhibiting acetylcholinesterase (AChE) would control symptoms of the disease.[1] 1.2. Acetylcholinesterase (AChE) Acetylcholinesterase (acetycholine acetylhydrolase, E.C. 3.1.1.7) [11] is involved in the hydrolysis of acetylcholine, an essential neurotransmitter of the central nervous system, into choline. This enzyme catalyzes the hydrolysis of the neurotransmitter acetylcholine at neuronal synapses, and at neuromuscular junctions, at the end of the signaling process. In certain neurological disorders such as Alzheimer’s disease, acetylcholinesterase is overactivated in the synapses so that levels of acetylcholine in the brains is significantly diminished, which leads to weakened neurotransmission and thereby memory loss and other adverse effects. 1.3. Chalcone Chalcones (1,3-diphenyl-2-propen-1-one) are open chain flavonoids with a 15-carbon structure arranged in a C6-C3-C6 configuration. They consist in two phenolic rings (A and B rings) connected by a 3C bridge with a double bond between α- and β-positions, which confers them a particularly singular structure.[16] 3
Figure 1.7. Structure and numbering of chalcone 1.4. Molecular Docking Molecular docking is an attractive scaffold to understand drugbiomolecular interactions for the rational drug design and discovery, as well as in the mechanistic study by placing a molecule (ligand) into the preferred binding site of the target specific region of the DNA/protein (receptor) mainly in a non-covalent fashion to form a stable complex of potential efficacy and more specificity. The information obtained from the docking technique can be used to suggest the binding energy, free energy and stability of complexes. At present, docking technique is utilized to predict the tentative binding parameters of ligand-receptor complex beforehand.[21] 1.5. In vitro screening for acetylcholinesterase inhibition AChE inhibitory activity was determined spectrophotometrically using the Ellman's colorimetric method. ACHE hydrolyzes the substrate ATCI to thiocholine and acetic acid. Thiocholine is allowed to react with DTNB, and this reaction resulted in the development of a yellow color. The color intensity of the product is measured at 405 nm, and it is proportional to the enzyme activity.[27] 1.6. Short-term memory impairment models Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. 4
Currently, short-term memory impairment models are widely used in the treatment of AD.[27] The Y-maze model and Novel Object Recognition model are quick and useful initial tests to study short-term memory. Chapter 2. CONDITION AND EXPERIMENTAL METHOD 2.1. Time and place of study Time: 1 11 2011 01/05/2017 Place: Labs of Department of Pharmacology, Department of Pharmaceutical, Department of Microbiology, Faculty of Pharmacy, Ho Chi Minh City Medicine and Pharmacy University. 2.2. Experimental content and method 2.2.1. Experimental content The molecular binding abilities of chalcone derivatives with ACHE were elucidated by docking procedure to predict the chalcone structure has strong in silico AChE acetylcholinesterase inhibitory activity. The potential chalcone compounds were synthesized by Claisen-Schmidt condensation reaction. These chalcone compounds are studied for their in vitro and in vivo AChE inhibitory activities. 2.2.2. Experimental method Molecular Docking Study The Protein Data Bank crystallographic structure of TcAChE(-)- Galantamine complex (pdb 1DX6)67 was used as receptor model in this study. The 3D structure of the crystallographic complex was rendered by means of BioSolveIT LeadIt. The active site was defined as all the important amino acid residues enclosed within a radius sphere of 6.5 Å centered by the bound ligand, galantamine. All unbound water molecules were eliminated and the structures of 5
amino acid residues were checked before re-establishing the active site of the enzyme. Docking process of 107 chalcone derivatives (35 normal chalcone derivatives, 24 heterocyclic chalcone derivatives, 32 benzylaminochalcone derivatives and 16 promazine chalcone derivatives) was performed in BioSolveIT LeadIt with the following options: the method in which base fragment placed in binding pocket was Triangle Matching; the maximum number of solutions per iteration was set to 1 000; the maximum number of solutions per fragmentation was set to 200; the number of poses to keep for further analysis of interaction was set to 10. The best conformation is the one that has the most minus docking score. This score was the total energy emitted from the formation of binding between the molecules and the active site. General Procedures for the Preparation of chalcone derivatives Claisen-Schmidt condensation reaction was applied to synthesize chalcone derivatives (Scheme 2.1). The reaction of acetophenone and benzaldehyde derivatives in KOH/MeOH was followed by an acidification with concentrated HCl provided chalcone derivatives with satisfactory yields after recrystallized from appropriate solvents. The structures and purities of the target compounds were conﬁrmed by UV, MS, IR, 1H-NMR and 13C-NMR spectra. Scheme 2.1. Claisen-Schmidt condensation reaction in chalcones synthesis[18] 6
In vitro Acetylcholinesterase inhibitory activity assay AChE inhibitory activities of chalcones were determined using purified acetylcolinesterase from electric eel (Sigma, Type VI) and acetylthiocholine iodide (Sigma) as a substrate with the colourimetric method of Ellman66. Galantamine, ATCI (acetylthiocholin iodide), and DTNB (5,5’-dithio-bis-nitro benzoic acid) were purchased from Sigma. This assay was performed in 96-well microtiter plates in the same condition for both chalcones and control substance (galantamine). In vivo Acetylcholinesterase inhibitory activity assay The best ACHE inhibitory chalcone derivative is tested for their ability to improve memory dysfunction in mice using two short-term memory impairment models: Y - maze model and Novel Object Recognition model based on Tran Phi Hoang Yen model (2007).[28] Chapter 3. RESULTS AND DISCUSSION 3.1. Molecular Docking Study 3.1.1. Re-docking result of co-crystallized ligand Re-docking results of galantamine showed that interactions made by re-docked conformations with the active site were resemble those of the original bound ligand in 1DX6. The RMSD values of re- docked conformations were < 1.5 Å (Table 3.1) indicated that the molecular model could be applied to explain the interactions of new ligands with the active site. 7
Table 3.1. Results of re-docking processes with co-crystallized ligands Ligand RMSD (Å) (1) separated from the complex (native form, not 0,4912 prepared). (2) separated from the complex and re-prepared using 0,5184 mentioned appropriate procedure. (3) built and prepared from the beginning. 0,5021 3.1.2 Docking results of chalcone derivatives 3.1.2.1 Docking results of 35 normal chalcone derivatives The docking process was performed successfully with all chalcone derivatives. The ways of change which are beneficial for the binding ability to acetylcholinesterase of chalcones are summarized and displayed in Fig 3.5. Fig 3.5. The ways of change which are beneficial for the binding ability to acetylcholinesterase of chalcones 8
The molecular docking studies elucidated the binding modes of chalcones to the active site of AChE quite precisely, and from which a structure – activity relationship was then drawn out. Thenceforward, we have the direction to design and synthesize new compounds that have high acetylcholinesterase inhibitory activities. 3.1.2.2. Docking results of 24 heterocyclic chalcone derivatives The docking results showed that chalcones containing thiophen moiety may increase the acetylcholinesterase inhibitory activity compaire with other heterochalcone. Beside, the substitution methoxy group(s) on B-ring (benzen ring) also lead to improve the bioactivity of the heterochalcone. X: thiophen moiety -OCH3 more beneficial than groups pyridin, furan moiety. Hình 3.11. The ways of change which are beneficial for the binding ability to acetylcholinesterase of heterocyclic chalcones This study was published in "Evaluation of acetylcholinesterase inhibitory activity of heterochalcones derivaties" in Journal of Medicine, Ho Chi Minh city, 2015. 3.1.2.3 Docking results of 32 benzylaminochalcone derivatives The docking process was performed successfully with all benzylaminochalcone derivatives. The ways of change which are beneficial for the binding ability to acetylcholinesterase of benzylaminochalcone derivatives are summarized and displayed in Fig 3.8. 9
- OH at position 2 or 3 N or O heterocyclic -OCH3 or -NO2 group on - OH (necessary for a ring B affect the binding high activity) orientation to the target. g tốt Fig 3.18. The ways of change which are beneficial for the binding ability to acetylcholinesterase of benzylamino chalcones From the docking results as fig 3.18, we have the direction to design and synthesize new benzylamino chalcones that have high acetylcholinesterase inhibitory activities. 3.1.2.4. Docking results of promazine chalcone derivatives Promazine chalcones are chalcone derivatives that ring A is replaced acepromazine. The docking process was performed with 16 promazine chalcone derivatives by BioSovelIT LeadIT. The ways of change which are beneficial for the binding ability to acetylcholinesterase of promazine chalcone derivatives are summarized and displayed in Fig 3.22. 10
-Cl group -OCH3 group -Br group -F group which have -Cl at position ortho Fig 3.22. The ways of change which are beneficial for the binding ability to acetylcholinesterase of promazine chalcone derivatives 3.2. Synthesis of chalcone derivatives 3.2.1. Synthesis of normal chalcone derivatives 20 Normal chalcone derivatives based on the orientation of docking results are synthesized by Claisen-Schmidt condensation reaction. Yield DerivativesName of derivatives (%) ST1 (E)-2-chloro-2’-hydroxychalcone 68 ST2 (E)-4-chloro-2’-hydroxychalcone 74 ST3 (E)-2,4-dichloro-2’-hydroxychalcone 74 ST4 (E)-2,3-dichloro-2’-hydroxychalcone 67 ST5 (E)-2’-hydroxy-2,4-dimethoxychalcone 71 ST6 (E)-2’-hydroxy-2,3-dimethoxychalcone 48 ST7 (E)-2’-hydroxy-3,4,5-trimethoxychalcone 67 ST8 (E)-2’-hydroxy-4-dimethylaminochalcone 87 ST9 (E)-2’-hydroxy-2,3,4’-trimethoxychalcone 58 ST10 (E)-2’-hydroxy-3,4,4’-trimethoxychalcone 62 11
ST11 (E)-2’-hydroxy-3,4,4’,5-tetramethoxychalcone 63 ST12 (E)-4-chloro-2’-hydroxy-4’-methoxychalcone 68 ST13 (E)-2’-hydroxy-2,4,4’,6’-tetramethoxychalcone 55 ST14 (E)-2’-hydroxy-3,4,4’,6’-tetramethoxychalcone 66 (E)-2’-hydroxy-2,3,4,4’,6’- ST15 72 pentamethoxychalcone (E)-4-chloro-2’-hydroxy-4’,6’- ST16 69 dimethoxychalcone ST17 (E)-4’-amino-2-chlorochalcone 66 ST18 (E)-4’-amino-4-chlorochalcone 70 ST19 (E)-4’-amino-4-nitrochalcone 76 ST20 (E)-3’,4-dinitrochalcone 60 Structure of all synthesized chalcone derivatives were conﬁrmed by UV, IR, 1H-NMR spectra and showed in addendum 6. 3.2.2. Synthesis of heterocyclic chalcone derivatives 24 heterocyclic chalcone derivatives are synthesized by Claisen- Schmidt condensation reaction. Yield DerivativesName of derivatives (%) (E)-1-(pyridin-2-yl)-3-[2-(hydroxy)phenyl]-2- D1 56 propen-1-one (E)-1-(pyridin-2-yl)-3-[4-(hydroxy)phenyl]-2- D2 65 propen-1-one (E)-1-(pyridin-2-yl)-3-[3-(hydroxy)phenyl]-2- D3 62 propen-1-one (E)-1-(pyridin-2-yl)-3-[4- D4 58 (dimethylamino)phenyl]-2-propen-1-one (E)-1-(pyridin-2-yl)-3-[3,4-(dimethoxy)phenyl]-2- D5 52 propen-1-one (E)-1-(pyridin-2-yl)-3-[3,4,5-(trimethoxy)phenyl]- D6 76 2-propen-1-one 12
(E)-1-(pyridin-2-yl)-3-[2,4-(dimethoxy)phenyl]-2- D7 63 propen-1-one (E)-1-(furan-2-yl)-3-[3,4-(dimethoxy)phenyl]-2- D8 51 propen-1-one (E)-1-(furan-2-yl)-3-[4-(methoxy)phenyl]-2- D9 64 propen-1-one (E)-1-(furan-2-yl)-3-[3,4,5-(trimethoxy)phenyl]-2- D10 68 propen-1-one (E)-1-(furan-2-yl)-3-[4-(hydroxy)phenyl]-2- D11 50 propen-1-one (E)-1-(furan-2-yl)-3-[3-(hydroxy)phenyl]-2- D12 54 propen-1-one (E)-1-(furan-2-yl)-3-[2-(hydroxy)phenyl]-2- D13 52 propen-1-one (E)-1-(furan-2-yl)-3-[3-(nitro)phenyl]-2-propen-1- D14 54 one (E)-1-(furan-2-yl)-3-[4-(dimethylamino)phenyl]- D15 62 2-propen-1-one (E)-1-(thiophen-2-yl)-3-[4-(hydroxy)phenyl]-2- D16 56 propen-1-one (E)-1-(thiophen-2-yl)-3-[3-(hydroxy)phenyl]-2- D17 52 propen-1-one (E)-1-(thiophen-2-yl)-3-[2-(hydroxy)phenyl]-2- D18 54 propen-1-one (E)-1-(thiophen-2-yl)-3-[4-(methoxy)phenyl]-2- D19 66 propen-1-one (E)-1-(thiophen-2-yl)-3-[2,4-(dimethoxy)phenyl]- D20 52 2-propen-1-one (E)-1-(thiophen-2-yl)-3-[3,4,5- D21 74 (trimethoxy)phenyl]-2-propen-1-one (E)-1-(thiophen-2-yl)-3-[3-(nitro)phenyl]-2- D22 52 propen-1-one (E)-1-(thiophen-2-yl)-3-[3-(nitro)phenyl]-2- D23 56 propen-1-one 13
(E)-1-(thiophen-2-yl)-3-[4- D24 60 (dimethylamino)phenyl]-2-propen-1-one 3.2.3. Synthesis of benzylaminochalcone derivatives The Claisen-Schmidt condensation reaction of 4'- aminoacetophenone and benzaldehyde derivatives provided 10 benzylaminochalcones. Yield DerivativesName of derivatives (%) (E)-1-(4-((2-hydroxylbenzyl)amino)phenyl)-3- A1 80,88 phenyl)prop-2-ene-1-one (E)-3-(2-chlorophenyl)-1-(4-((2- A2 88 hydroxylbenzyl)amino)phenyl)prop-2-ene-1-one (E)-3-(4-chlorophenyl)-1-(4-((2- A3 81,60 hydroxylbenzyl)amino)phenyl)prop-2-ene-1-one (E)-3-(4-nitrophenyl)-1-(4-((2- A4 60 hydroxylbenzyl)amino)phenyl)prop-2-ene-1-one (E)-3-(2,3-dimethoxyphenyl)-1-(4-((2- A5 81,51 hydroxylbenzyl)amino)phenyl)prop-2-ene-1-one (E)-3-(3,4-dimethoxyphenyl)-1-(4-((2- A6 58,85 hydroxylbenzyl)amino)phenyl)prop-2-ene-1-one (E)-3-(2,4-dimethoxyphenyl)-1-(4-((2- A7 80 hydroxylbenzyl)amino)phenyl)prop-2-ene-1-one (E)-1-(4-((2-hydroxylbenzyl)amino)phenyl)-3- A8 82,71 (pyridin-2-yl)prop-2-ene-1-one (E)-1-(4-((2-hydroxylbenzyl)amino)phenyl)-3- A9 69,23 (pyridin-4-yl)prop-2-ene-1-one (E)-3-(furan-2-yl)-1-(4-((2- A10 76,30 hydroxylbenzyl)amino)phenyl)prop-2-ene-1-one 14
10 Benzylaminochalcone were recognised as new compounds based on Scifinder (2016). This study was published in "Synthesis of novel chalcones as acetylcholinesterase inhibitors" in Applied Sciences, 2016.[44] 3.2.4. Synthesis of promazine chalcone derivatives 10 promazine chalcones (AC1-AC10) based on the orientation of the docking results are synthesized by Claisen-Schmidt condensation reaction. Yield DerivativesName of derivatives (%) (E)-3-(2-chlorophenyl)-1-(10-(3- AC1 (dimethylamino)propyl)-10H-phenothiazin-2-yl)- 81% 3-phenylprop-2-en-1-one (E)-3-(4-chlorophenyl)-1-(10-(3- AC2 (dimethylamino)propyl)-10H-phenothiazin-2-yl)- 78% 3-phenylprop-2-en-1-one (Z)-3-(2,4-dichlorophenyl)-1-(10-(3- AC3 (dimethylamino)propyl)-10H-phenothiazin-2-yl)- 62% 3-phenylprop-2-en-1-one (E)-1-(10-(3-(dimethylamino)propyl)-10H- AC4 phenothiazin-2-yl)-3-(4-fluorophenyl)prop-2-en-1- 57% one (E)-3-(3-bromophenyl)-1-(10-(3- AC5 (dimethylamino)propyl)-10H-phenothiazin-2-yl)- 51% 3-phenylprop-2-en-1-one (E)-3-(2-chloro-6-fluorophenyl)-1-(10-(3- AC6 (dimethylamino)propyl)-10H-phenothiazin-2-yl)- 43% 3-phenylprop-2-en-1-one (E)-1-(10-(3-(dimethylamino)propyl)-10H- AC7 58% phenothiazin-2-yl)-3-(2- 15
trifluoromethyl)phenyl)prop-2-en-1-one (E)-1-(10-(3-(dimethylamino)propyl)-10H- AC8 phenothiazin-2-yl)-3-(3-methoxyphenyl)prop-2- 43% en-1-one (E)-1-(10-(3-(dimethylamino)propyl)-10H- AC9 phenothiazin-2-yl)-3-(4-methoxyphenyl)prop-2- 41% en-1-one (E)-1-(10-(3-(dimethylamino)propyl)-10H- AC10 phenothiazin-2-yl)-3-(3,4,5- 51% trimethoxyphenyl)prop-2-en-1-one 9 Promazine chalcones (AC1-AC8 and AC10) were recognised as new compounds based on Scifinder (2017). 3.3. In vitro Acetylcholinesterase inhibitory activity assay 3.3.1. In vitro Acetylcholinesterase inhibitory activity assay of normal chalcone derivatives The IC50 values of 20 normal chalcone derivatives for AChE inhibition are indicated in Table 3.13. Bảng 3.13. The IC50 values (%) of 20 normal chalcone derivatives for AChE inhibition Docking Docking IC50 Derivatives score Derivatives IC50 (µM) score (µM) (kJ/mol) (kJ/mol) ST1 92,42 -27,33 ST11 > 500 -19,41 ST2 52,71 -34,46 ST12 > 500 -19,41 ST3 51,01 -29,98 ST13 349,09 -20,27 ST4 62,37 -23,47 ST14 > 500 -15,40 ST5 86,45 -26,43 ST15 > 500 -18,37 16
ST6 > 500 -16,50 ST16 213,14 -20,54 ST7 > 500 -17,50 ST17 36,10 -36,29 ST8 > 500 -18,30 ST18 > 500 -14,53 ST9 190,98 -24,28 ST19 > 500 -19,41 ST10 129,90 -25,90 ST20 > 500 -21,25 There was a good correlation between docking scores and bioactivities of studied chalcone compounds. Among the studied compounds, S17 showed the strongest interaction with its target. Hình 3.35. 2D interactions between S17 and the active site of AChE (pdb id: 1dX6) 4.3.2 In vitro Acetylcholinesterase inhibitory activity assay of heterocyclic chalcone derivatives The results showed that heterocyclic chalcones containing thiophen moiety may increase the acetylcholinesterase inhibitory activity compaire with other heterochalcone. Among the studied heterocyclic chalcones, D21 containing thiophen moiety and 3 - OCH3 groups has the best IC50 (114,8 µM). This study was published in "Evaluation of acetylcholinesterase inhibitory activity of heterochalcones derivaties" in Journal of Medicine, Ho Chi Minh 17
city, 2015.[43] 4.2.3 Khảo sát khả năng kháng acetylcholinesterase của các dẫn chất benzylaminochalcone The IC50 values of 10 benzylaminochalcone derivatives for AChE inhibition are indicated in Table 3.18. Table 3.18. The IC50 values of 10 benzylaminochalcone derivatives for AChE inhibition Derivatives IC50 (µM) pIC50 Docking score (kJ/mol) A1 160.33 -2.21 −18.23 A2 121.91 -2.09 −20.34 A3 23.71 -1.37 −20.55 A4 31.57 -1.50 −21.89 A5 121.61 -2.08 −20.56 A6 23.02 -1.36 −19.32 A7 147.84 -2.17 −18.34 A8 116.34 -2.07 −20.07 A9 38.97 -1.59 −21.42 A10 89.19 -1.95 −21.22 Galantamine 1.27 0.10 −23.1 Compounds with ring B bearing pyridin-4-yl, 4-nitrophenyl, 4-chlorophenyl and 3,4-dimethoxyphenyl moieties were discovered to exhibit significant inhibitory activities against acetylcholinesterase, with IC50 values ranging from 23 to 39 µM. Among of them, (E)-3-(3,4-dimethoxyphenyl)-1-(4-((2- hydroxylbenzyl)amino) phenyl)prop-2-ene-1-one (A6) has a strongest bioactivity as acetyl-cholinesterase inhibitors (IC50 23,02 µM). This result was published in "Synthesis of novel chalcones as acetylcholinesterase inhibitors" in Applied Sciences, 2016.[44] 18