|Year : 2017 | Volume
| Issue : 5 | Page : 353-363
Facile one-pot four-component synthesis of 3,4-dihydro-2-pyridone derivatives: Novel urease inhibitor scaffold
Arash Modarres Hakimi1, Negar Lashgari2, Shabnam Mahernia1, Ghodsi Mohammadi Ziarani3, Massoud Amanlou1
1 Drug Design & Development Research Centre and Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, I.R. Iran
2 School of Chemistry, College of Science, University of Tehran, Tehran, I.R. Iran
3 Department of Chemistry, Alzahra University, Tehran, I.R. Iran
|Date of Web Publication||13-Sep-2017|
Drug Design & Development Research Centre and Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
In the current study, a series of 3,4-dihydro-2-pyridone derivatives were synthesized in a one-pot four- component reaction of Meldrum's acid, benzaldehyde derivatives, methyl acetoacetate, and ammonium acetate. SiO2-Pr-SO3H was used as an efficient catalyst for the synthesis of the target compounds under solvent-free conditions. The most probable mechanism for this reaction has been discussed. The advantages of this methodology are high product yields, being environmentally benign, short reaction times, and easy handling. Eight 2-pyridinone derivatives were evaluated for their inhibitory activities against Jack bean urease. Molecular docking study of the synthesized compounds was also evaluated. All compounds showed good activities against urease and among them, 4-(4-nitrophenyl)-5-methoxycarbonyl-6-methyl-3,4- dihydropyridone (5a) showed the most potent activity (IC50 = 29.12 µM), more potent than hydroxyurea as the reference drug (IC50 = 100.0 µM). Also, the results from docking studies were in good agreement with those obtained with in vitro assay. According to the docking studies methionine (Met) 637 and nitro phenyl ring cause n-π interaction between lone pair of sulfur atom and π aromatic ring. Moreover, hydrophobic interactions existed between compound 5a and alanine (ALA) 636, ALA 440, and isoleucine 411. The results indicated that the inhibitory activities increased with the increase of electron withdrawing ability of the groups despite a less important role of lipophilicity in increasing the inhibitory activity.
Keywords: Multicomponent reaction; Urease inhibitory activity; 3,4-Dihydro-2-pyridone derivatives; SiO2-Pr-SO3H
|How to cite this article:|
Hakimi AM, Lashgari N, Mahernia S, Ziarani GM, Amanlou M. Facile one-pot four-component synthesis of 3,4-dihydro-2-pyridone derivatives: Novel urease inhibitor scaffold. Res Pharma Sci 2017;12:353-63
|How to cite this URL:|
Hakimi AM, Lashgari N, Mahernia S, Ziarani GM, Amanlou M. Facile one-pot four-component synthesis of 3,4-dihydro-2-pyridone derivatives: Novel urease inhibitor scaffold. Res Pharma Sci [serial online] 2017 [cited 2017 Sep 19];12:353-63. Available from: http://www.rpsjournal.net/text.asp?2017/12/5/353/213980
| Introduction|| |
In 1926, crystallized urease from Jack bean urease (EC 18.104.22.168) by James B. Sumner was the first nickel-containing enzyme. The life cycle, pathogenesis of Helicobacter pylori ori) is very appertaining to the presence of nickel in its environment .
Urease catalyzes hydrolysis of urea to ammonia and carbon dioxide which neutralizes gastric acid and increases pH in stomach. Urease plays an important role in the nitrogen metabolism, acid resistance, and virulence of H. pylori and represented up to 10% of total protein content of the bacteria ,,.
H. pylori have been colonized in the gastric epithelium of humans for at least 58,000 years.
H. pylori infection leads to chronic gastritis that most people have no symptoms but is the main risk factor for peptic ulcer, duodenal ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and adenocarcinoma ,,. Existing therapeutic regimens have lost some efficacy due to high level of antibiotic resistance to H. pylori and poor patient compliance.
Urease activity control through the use of inhibitors can overcome these shortcomings ,,. So far, several urease inhibitors are presented; [Figure 1] shows the chemical structure of some of them.
Multicomponent reactions (MCR) have become popular in organic, medicinal, and combinatorial chemistry because they address both diversity and complexity in organic synthesis. MCR is defined as a process in which three or more different components are combined to yield ideally a single product. Such procedures reduce time and save both energy and starting materials ,,.
The current literature reveals that 1,4- dihydropyridine derivatives (1,4-DHP) exhibit interesting biological activities such as anti-inflammatory , antitubercular , antiatherosclerotic , and anticancer activities . 1,4-DHP derivatives are also a class of heterocyclic compounds well-known as Ca2+ channel blockers . 2-Pyridones are structurally very similar to 1,4-DHP. Compounds with such structures are found to possess various biological and pharmacological properties ,,. Although several different methods have been reported for the preparation of 2-pyridone derivatives, development of new synthetic methods for efficient synthesis of this class of compounds is still an interesting challenge.
Recently, the emphasis on green chemical principles introduced some significant advances in organic synthesis ,. In this regard, heterogeneous catalysts have found considerable interest in organic reactions, since these catalysts can be recovered and reused several times after the reaction without significant loss of reactivity. Reactions with these catalysts are generally clean and selective and give high yields of products.
In continuation of our research on the multicomponent synthesis of heterocyclic compounds of biological importance ,,,, herein we wish to report a green and efficient procedure for the synthesis of 3,4-dihydro-2- pyridone derivatives in the presence of SiO2-Pr-SO3H as a heterogeneous acid catalyst under solvent-free conditions with potential urease inhibitory activity.
| Materials and Methods|| |
All commercially available chemicals were purchased from Merck Company (Germany) and used without further purification. IR spectra were recorded from KBr disk using a FT-IR Bruker Tensor 27 instrument (USA). Melting points measured by using the capillary tube method with an electro thermal 9200 apparatus (Bibby Scientific Limited, Staffordshire, UK) are uncorrected. The 1H NMR (250 MHz) and 13C NMR (125 MHz) were run on a Bruker DPX (USA) at 250 MHz in CDCl3 and 125 MHz in D2O using tetramethylsilane as internal standard. GC- Mass analysis was performed on a GC-Mass model: 5973 network mass selective detector, GC 6890 Agilent Technologies (USA).
Preparation of catalyst (SiO2-Pr-SO3H)
SiO2-Pr-SO3H was prepared according to our previous report  and was used as a solid acid catalyst in the following reaction.
General procedure for the synthesis of 2- pyridone derivatives 5a-5h
The SiO2-Pr-SO3H (0.02 g) was activated in vacuum at 100°C and after cooling the catalyst to room temperature, Meldrum's acid 1 (0.43 g, 3 mmol), methyl acetoacetate 2 (0.32 mL, 3 mmol), aromatic aldehyde 3 (3 mmol), and ammonium acetate 4 (0.38 g, 5 mmol) were added. The mixture was heated under solvent-free condition at 140°C for the time reported in [Table 1]. The progress of reaction was monitored by thin layer chromatography. The generated solid product was dissolved in hot ethanol, filtered for removing the catalyst, and then the filtrate was cooled to afford the pure product.
|Table 1: Synthesis of 3,4-dihydro-2-pyridones 5a-5h under optimized conditions.|
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4-(4-Nitrophenyl)-5-methoxycarbonyl-6- methyl-3,4-dihydropyridone (5a)
Mp 210-212°C; IR (KBr): 3375, 1697, 1638, 1517, 1349 cm-1; 1H NMR (500 MHz, D2O): δ 8.14-8.16 (2H, m, ArH), 7.56 (1H, s, NH), 7.25-7.35 (2H, m, ArH), 4.35 (1H, d, J = 8.0 Hz), 3.66 (3H, s, OCH3), 3.01 (1H, dd, J = 16.5 Hz, 8.0 Hz), 2.67 (1H, dd, J = 16.5 Hz, 8.0 Hz), 2.45 (3H, s, CH3) ppm; 13C NMR (125 MHz, D2O): δC 19.3, 37.5, 37.9, 51.6, 105.8, 124.1, 127.6, 136.5, 140.2, 143.3, 147.2, 149.4, 166.7, 169.7; MS (EI, m/z): 290 (M+).
4-(3-Nitrophenyl)-5-methoxycarbonyl-6- methyl-3,4-dihydropyridone (5b)
Mp 204-206°C; IR (KBr): 3351, 1704, 1648, 1528, 1348 cm-1; 1H NMR (250 MHz, CDQ3): δ 8.03-8.35 (3H, m, ArH, NH), 7.24-7.73 (2H, m, ArH), 4.34 (1H, dd, J = 8.0 Hz, 1.5 Hz), 3.66 (3H, s, OCH3), 3.01 (1H, dd, J = 16.4 Hz, 8.0 Hz), 2.66 (1H, dd, J = 16.4 Hz, 1.5 Hz), 2.45 (3H, s, CH3) ppm; MS (EI, m/z): 290 (M+).
4-(4-Methoxyphenyl)-5-methoxycarbonyl-6- methyl-3,4-dihydropyridone (5c)
Mp 188-190°C; IR (KBr): 3217, 1691, 1631, 1249, 1085 cm-1; MS (EI, m/z): 275 (M+).
4-Phenyl-5-methoxycarbonyl-6-methyl-3,4- dihydropyridone (5d)
Mp 193-194°C; IR (KBr): 3218, 1696, 1638, 1282, 1086 cm-1; MS (EI, m/z): 245 (M+).
4-(4-Chlorophenyl)-5-methoxycarbonyl-6- methyl-3,4-dihydropyridone (5e)
Mp 195-198°C; IR (KBr): 3218, 1694, 1633, 1281, 1082 cm-1; MS (EI, m/z): 279 (M+).
4-(2,4-Dimethoxyphenyl)-5-methoxycarbonyl- 6-methyl-3,4-dihydropyridone (5f)
Mp 140-141°C; IR (KBr): 3225, 1694, 1611, 1260, 1036 cm-1; 1H NMR (250 MHz, CDCl3): δ 8.20 (1H, br s, NH), 7.26 (1H, s, ArH), 7.04 (1H, d, J = 9.25 Hz, ArH), 6.86 (1H, d, J = 5.25 Hz, ArH), 4.63 (1H, dd, J = 8.3 Hz, 1.9 Hz), 3.75 (3H, s, OCH3), 3.70 (3H, s, OCH3), 3.46 (3H, s, OCH3), 2.80 (1H, dd, J = 16.5 Hz, 8.3 Hz), 2.42 (1H, dd, J = 16.5 Hz, 1.9 Hz), 1.50 (3H, s, CH3) ppm; MS (EI, m/z): 305 (M+).
4-(2,4-Dichlorophenyl)-5-methoxycarbonyl-6- methyl-3,4-dihydropyridone (5g)
Mp 203-206°C; IR (KBr): 3229, 1705, 1642, 1591, 800 cm-1; 1H NMR (250 MHz, CDCl3): δ 8.79 (1H, br s, NH), 7.40 (1H, s, ArH), 7.14 (1H, d, J = 7.5 Hz, ArH), 6.96 (1H, d, J = 8.25 Hz, ArH), 4.64 (1H, dd, J = 8.3 Hz, 1.9 Hz), 3.60 (3H, s, OCH3), 2.94 (1H, dd, J = 16.5 Hz, 8.3 Hz), 2.78 (1H, dd, J = 16.5 Hz, 1.9 Hz), 2.45 (3H, s, CH3) ppm; MS (EI, m/z):313 (M+).
4-(2-Methoxyphenyl)-5-methoxycarbonyl-6- methyl-3,4-dihydropyridone (5h)
Mp 202-205°C; IR (KBr): 3240, 1699, 1634, 1245, 1051 cm-1; 1H NMR (250 MHz, CDQ3): δ 8.15 (1H, br s, NH), 7.26 (1H, d, J = 10 Hz, ArH), 7.19 (1H, d, J = 7.75 Hz, ArH), 6.79-6.96 (2H, m, ArH), 4.57 (1H, dd, J = 8.3 Hz, 1.9 Hz), 3.83 (3H, s, OCH3), 3.60 (3H, s, OCH3), 2.87 (1H, dd, J = 16.5 Hz, 8.3 Hz), 2.77 (1H, dd, J = 16.5 Hz, 1.9 Hz), 2.42 (3H, s, CH3) ppm; MS (EI, m/z): 275 (M+).
Urease inhibitory assay
Urease (EC 22.214.171.124) from Jack beans and sodium nitroprusside were purchased from Sigma (USA). Ultra-pure water, (HPLC grade, Duksan, Korea) was used throughout the experiments. Measuring the release of ammonia by a modification of the Berthelot reaction determined the urease inhibitory activity of the synthesized compound ,. The reaction mixture consisted of urea (850 µL, 25 mM), 15 µL of urease enzyme solution (2 mg/mL) and 135 µL of the test compounds of various concentrations in 100 mM sodium phosphate buffer (pH 7.4). Mixture was pre- incubated for 30 minutes in water bath at 37°C. After pre-incubation, 100 µL of mixture were mixed with 500 µL of phenol reagent (contained 2.5 mg of sodium nitroprusside and 0.5 g phenol in 50 mL of distilled water) and 500 µL of alkaline reagent containing 820 µL of sodium hypochlorite 5% and 250 mg sodium hydroxide in 50 mL of distilled water. After further 30 min incubation at 37°C, absorbance was measured at 625 nm.
The inhibition percentage (I (%)) was calculated by the following equation:
I (%) = 100 - ((AJNH/AB) × 100)
where, AJNH is the absorbance of the tested sample and AB is the absorbance of the solvent in the presence of enzyme. The IC50 values were calculated using GraphPad Prism 6 software. All experiments were performed in triplicate and hydroxyurea was used as the standard compound which is already confirmed to have significant inhibitory characteristics for urease.
Eight compounds have sketched by Marvin sketch applet (Marvin package, Chemaxon Company, Hungary). Afterward polar hydrogens and rotatable bonds was added with AutoDockTools 1.5.6 (ADT). The crystal structure of H. pylori urease enzyme with resolution of 2.05 Å was downloaded from the protein data bank (3LA4, http://www.pdb.org) and was used for docking studies ,. In the present study, the metal ions and non- standard protein residues (KCX and CME) were contained within the binding site specification but before initiating the docking simulations, all ligands and all water molecules were removed from urease structure file with ADT. A grid map was used consisted of 70 × 70 × 70 Å points around the active site and calculated by AutoGrid 4.2. The center of the grid was set to the mean coordinates of the two Ni2+ ions in the a chain of the urease enzyme. Docking with a maximum number of 25 × 106 energy evaluations were performed by AutoDock 4.2. The other docking parameters were set to default values. Once clustering analysis was performed, selection of the conformation based on the most favorable binding energy was done.
| Results|| |
In the present work, we explored the catalytic activity of SiO2-Pr-SO3H toward the clean one-pot synthesis of pyridone derivatives (Scheme 1) [Additional file 1]. At first, the effect of different solvents on the reaction times and yields of the product 5d was examined. For this purpose, the model reaction of Meldrum's acid 1, methyl acetoacetate 2, benzaldehyde 3, and ammonium acetate 4 was investigated in various solvents such as H2O, MeCN, EtOH, EtOH/H2O (1:1), and solvent-free system [Table 2]. It was found that solvent-free medium was the most effective condition in terms of reaction time (32 min) and yield of compound 5d (93%). To determine the optimum temperature, we investigated the model reaction at room temperature, 50°C, 140°C, and the best result was obtained at 140°C. Then, in regard to library construction, we extended our study with different substituted aldehydes under solvent-free condition at 140°C in the presence of a catalytic amount of SiO2-Pr-SO3H. The results are summarized in [Table 1]. A series of pyridine derivatives were successfully synthesized in high yields and appropriate times. It was reported that this reaction could be observed when the aliphatic aldehydes were used as starting materials .
The structures of some products were characterized by spectral analysis and melting points were compared with values reported in the literature [Table 1].
This reaction may occur via a condensation, addition, cyclization, and elimination mechanism (Scheme 2) [Additional file 2]. After protonation of carbonyl groups of Meldrum's acid and benzaldehyde derivatives by the solid acid catalyst, a Knoevenagel condensation occurs between Meldrum's acid and the corresponding benzaldehyde to afford the intermediate 6. Then, intermediate 6 undergoes a Michael-type addition with enamino compound 7 (resulting from the reaction of ammonia and methyl acetoacetate). Finally, intramolecular cyclodehydration in intermediate 8 provides the desired product 5.
The NMR experiment also confirmed the formation of the pyridone rings. The 1H NMR spectrum of compound 5b shows the two protons on C-3 as a part of an ABX system which was confirmed by a doublet of doublet at δ = 4.34 corresponding to the proton on C-4 due to the splitting by coupling with the protons on C-3 (J = 8.0 Hz and J = 1.5 Hz). Due to the greater acidity of Meldrum's acid (pKa = 9.97) in comparison with methyl acetoacetate (pKa = 11.0), we do not obtain 1,4-dihydropyridines.
[Table 3] illustrates a comparison of the effectiveness of various catalysts used in the synthesis of 2-pyridone derivatives. The results illustrates that SiO2-Pr-SO3H provided an efficient route to access these compounds. Because of green chemistry viewpoint, the reusability of the catalyst was investigated under optimized conditions for the synthesis of the model compound 5d.
|Table 3: Comparison of SiO2-Pr-SO3H and various catalysts in the synthesis of 5d.|
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The process of recycling was completed four times and no significant decrease in activity was observed. The yields for the four runs were found to be 93, 87, 81, and 76%, respectively.
Eight 2-pyridinone derivatives were evaluated for their inhibitory activities against
Jack bean urease which is similar to H. pylori urease in its structure. All of these compounds showed good activity against urease and four of test compounds (5a, 5b, 5e, and 5g) showed potent urease inhibitory activities, in comparison to hydroxyurea as a standard inhibitor with IC50 equal to 100 µM [Table 4].
|Table 4: Inhibitory concentration, binding energy and two-dimensional interaction of 3,4-dihydro-2-pyridone derivatives with urease active site.|
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Compound 5a showed the most potent inhibitory activity against urease (IC50 = 29.12 µM). Compounds containing nitro group and chlorine showed greater inhibitory. This result indicated that the inhibitory activities increased with the increase of electron withdrawing ability of the groups despite a less important role of lipophilicity in increasing the inhibitory activity.
| Discussions|| |
To investigate the binding effects between compound 5a and the H. pylori urease the molecular docking study was performed. In the binding model nitro group coordinates with both nickel ions and also asparagine (ASP) 637 and KCX 490. Met 637, CME 592, and histidine (HIS) 492 formed hydrogen bonds and also oxygen of glutamine (GLN) 635 formed a hydrogen bond with pyridine NH.
According to docking studies Met 637 and nitrophenol ring causes π-π interaction between sulfur atom of amino acid and the ring. Moreover, hydrophobic interactions existed between compound 5a and ALA 636, ALA 440, and isoleucine (ILE) 411.
Shifting of nitro group from para to meta position in compound 5b caused less hydrogen bonds and therefore less inhibitory activity (IC50 = 48.84 μM) compare to compound 5a. This is probably because of different molecule orientation in active site.
In compound 5e, which nitro group substituted with Cl result in just two hydrogen bonds with MET 637 and CME 592. Cl and ALA 636 showed hydrophobic interactions and also an n-π interaction between ring and MET 637 (IC50 = 84.08 μM). Adding another Cl to ortho position of the ring in compound 5g slightly improved inhibitory activity due to increase in hydrophobic interactions between two Cl and MET 588, ALA 440, leucine (LEU) 589, Met 637, and CME 592 (IC50 = 81.99 μM).
Although compound 5d did not coordinate with nickel ions formed four hydrogen bonds with ALA 636, MET 637, CME 592, and arginine (ARG) 439 (IC50 = 131.3 μM). Methoxy group added to para position of the ring in compound 5c (IC50 = 119.9 μM) and two methoxy group to para and ortho positions of ring in compound 5f (IC50 = 102.5 μM) resulted in increasing hydrophobic interactions between the compounds and amino acids of the H. pylori urease.
The confirmation of compound 5h in the active site of urease led to less inhibition activity (IC50 = 158.5 μM) in comparison to other compounds.
| Conclusions|| |
In conclusion, we have demonstrated that SiO2-Pr-SO3H is an efficient catalyst for the synthesis of 3,4-dihydro-2-pyridone derivatives under solvent-free conditions. High yields of the products, short reaction times, and simplicity of the system make it an improved protocol in comparison with existing methods. We evaluated inhibitory activity of synthesized compounds through jack bean urease and all of them showed inhibitory activity against urease. Compound 5a showed good inhibition compared to hydroxyurea .
| Acknowlegements|| |
We gratefully acknowledge financial support of the Research Council of Alzahra University and University of Tehran and Tehran University of Medical Sciences.
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[Table 1], [Table 2], [Table 3], [Table 4]