Facile one-pot four-component synthesis of 3,4-dihydro-2-pyridone derivatives: novel urease inhibitor scaffold

Arash Modarres Hakimi, Negar Lashgari, Shabnam Mahernia, Ghodsi Mohammadi Ziarani, Massoud Amanlou

Abstract


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

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Palizban A, Saghaie L. Synthesis and evaluation of the complex-forming ability of hydroxypyranones and hydroxypyridinones with Ni (II) as possible inhibitors for urease enzyme in Helicobacter pylori. Res Pharm Sci. 2016;11(4):332-342.

Mobley HLT, Hausinger RP. Microbial ureases: significance, regulation, and molecular characterization. Microbiol Rev. 1989;53(1):85-108.

Kusters JG, van Vliet AHM, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev. 2006;19(3):449-490.

Bauerfeind P, Garner R, Dunn BE, Mobley HL. Synthesis and activity of Helicobacter pylori urease and catalase at low pH. Gut. 1997;40(1):25-30.

Wroblewski LE, Peek RM Jr, Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010;23(4):713-739.

Salama NR, Hartung ML, Muller A. Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol. 2013;11:385-399.

Peek RM Jr, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol. 2006;208(2):233-248.

Khan KM, Wadood A, Ali M, Zia-Ullah, Ul-Haq Z, Lodhi MA, et al. Identification of potent urease inhibitors via ligand- and structure-based virtual screening and in vitro assays. J Mol Graph Model. 2010;28(8):792-798.

Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon ATR, Bazzoli F, et al. Management of Helicobacter pylori infection-- the maastricht IV/ florence consensus report. Gut. 2012;61(5):646-664.

Barbosa LCA, Oliveira FM, Valente VMM, Demuner AJ, Maltha CRA, Oliveros-Bastidas AJ. Structure–activity relationship of pyridin-2(1H)-ones derivatives as urease inhibitors. J Pharm Res. 2012;5(12):5326-5333.

Mohammadi Ziarani G, Moradi R, Lashgari N. Synthesis of spiro-fused heterocyclic scaffolds through multicomponent reactions involving isatin. Arkivoc. 2016;i:1-81.

Dömling A, Wang W, Wang K. Chemistry and biology of multicomponent reactions. Chem Rev. 2012;112(6):3083-3135.

de Graaff C, Ruijter E, Orru RV. Recent developments in asymmetric multicomponent reactions. Chem Soc Rev. 2012;41(10):3969-4009.

Tale RH, Rodge AH, Hatnapure GD, Keche AP, Patil KM, Pawar RP. The synthesis, anti-inflammatory, and anti-microbial activity evaluation of new series of 4-(3-arylureido)phenyl-1,4-dihydropyridine urea derivatives. Med Chem Res. 2013;22:1450-1455.

Desai NC, Trivedi AR, Somani HC, Bhatt KA. Design, synthesis, and biological evaluation of 1,4-dihydropyridine derivatives as potent antitubercular agents. Chem Biol Drug Des. 2015;86(3):370-377.

Carosati E, Ioan P, Micucci M, Broccatelli F, Cruciani G, Zhorov BS, et al. 1,4-dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (Part 2): action in other targets and antitargets. Curr Med Chem. 2012;19(25):4306-4323.

Radadiya A, Khedkar V, Bavishi A, Vala H, Thakrar S, Bhavsar D, et al. Synthesis and 3D-QSAR study of 1,4-dihydropyridine derivatives as MDR cancer reverters. Eur J Med Chem. 2014;74:375-387.

Kang S, Cooper G, Dunne SF, Luan CH, James Surmeier D, Silverman RB. Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics. Bioorg Med Chem. 2013;21(14):4365-4373.

Collins I, Moyes C, Davey WB, Rowley M, Bromidge FA, Quirk K, et al. 3-Heteroaryl-2-pyridones: Benzodiazepine site ligands with functional selectivity for α2/α3-subtypes of human gabaa receptor-ion channels. J Med Chem. 2002;45(9):1887-1900.

Desai NC, Dodiya AM, Shihory NR. A search of novel antimicrobial based on benzimidazole and 2-pyridone heterocycles. Med Chem Res. 2012;21(9):2579-2586.

Desai NC, Rajpara KM, Joshi VV. Synthesis of pyrazole encompassing 2-pyridone derivatives as antibacterial agents. Bioorg Med Chem Lett. 2013;23(9):2714-2717.

Jessop PG. Searching for green solvents. Green Chem. 2011;13:1391-1398.

Sheldon RA. Fundamentals of green chemistry: efficiency in reaction design. Chem Soc Rev. 2012;41:1437-1451.

Mohammadi Ziarani G, Faramarzi S, Asadi S, Badiei A, Bazl R, Amanlou M. Three-component synthesis of pyrano[2,3-d]-pyrimidine dione derivatives facilitated by sulfonic acid nanoporous silica (SBA-Pr-SO3H) and their docking and urease inhibitory activity. Daru. 2013;21(1):3. doi: 10.1186/2008-2231-21-3.

Lashgari N, Mohammadi Ziarani G, Badiei A, Zarezadeh-Mehrizi M. Application of sulfonic acid functionalized sba-15 as a new nanoporous acid catalyst in the green one-pot synthesis of spirooxindole-4h-pyrans. J Heterocycl Chem. 2014;51(6):1628-1633.

Mohammadi Ziarani G, Hosseini Mohtasham N, Lashgari N, Badiei A. Efficient one-pot synthesis of 2H-indazolo[2,1-b]phthalazinetrione derivatives with amino-functionalized nanoporous silica (SBA-Pr-NH2) as catalyst. Res Chem Intermed. 2015;41:7581-7591.

Mohammadi Ziarani G, Moradi R, Badiei A, Lashgari N, Moradi B, Abolhasani Soorki A. Efficient green synthesis of 3,3-di(indolyl)indolin-2-ones using sulfonic acid functionalized nanoporous SBA-Pr-SO3H and study of their antimicrobial properties. J Taibah Univ Sci. 2015;9(4):555-563.

Mohammadi Ziarani G, Badiei A, Lashgari N, Pourjafar T, Farahani Z. Silica-based sulfonic acid (SiO2-Pr-SO3H): an efficient catalyst in the green one-pot synthesis of 3,4-dihydropyrimidinones/thiones. Bulg Chem Commun. 2015;46(42):719-723.

Nabati F, Mojab F, Habibi-Rezaei M, Bagherzadeh K, Amanlou M, Yousefi B. Large scale screening of commonly used Iranian traditional medicinal plants against urease activity. Daru. 2012;20:72-81.

Vosooghi M, Farzipour S, Saeedi M, Shareh NB, Mahdavi M, Mahernia Sh, et al. Synthesis of novel 5-arylidene (thio)barbituric acid and evaluation of their urease inhibitory activity. J Iran Chem Soc. 2015;12(8):1487-1491.

Azizian H, Nabati F, Sharifi A, Siavoshi F, Mahdavi M, Amanlou M. Large-scale virtual screening for the identification of new helicobacter pylori urease inhibitor scaffolds. J Mol Model. 2012;18(7):2917–2927.

Ahari-Mostafavi M, Sharifi A, Mirzaei M, Amanlou M. Novel and versatile methodology for synthesis of b-aryl-bmercapto ketone derivatives as potential urease inhibitors. J Iran Chem Soc. 2014;11:1113–1119.

Fu G-Y, Zhang X-L, Sheng S-R, Wei M-H, Liu X-L. Rapid microwave-assisted liquid-phase synthesis of 4-substituted-5-methoxycarbonyl-6-methyl-3,4-dihydropyridones on poly(ethylene glycol) support. Synth Commun. 2008;38(8):1249-1258.

Ruiz E, Rodríguez H, Coro J, Salfrán E, Suárez M, Martínez-Alvarez R, et al. Ultrasound-assisted one-pot, four component synthesis of 4-aryl 3,4-dihydropyridone derivatives. Ultrason Sonochem. 2010;18(1):32-36.

Rodríguez H, Suarez M, Pérez R, Petit A, Loupy A. Solvent-free synthesis of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones under microwave irradiation. Tetrahedron Lett. 2003;44(18):3709-3712.

Svetlik J, Goljer I, Turecek F. Oxygen-bridged tetrahydropyridines, hexahydropyridines, and dihydropyridones via a Hantzsch-like synthesis with 4-(2-hydroxyphenyl)but-3-en-2-one. J Chem Soc, Perkin Trans 1. 1990;5:1315-1318.

Morales A, Ochoa E, Suárez M, Verdecia Y, González L, Martín N, et al. Novel hexahydrofuro[3,4-b]-2(1H)-pyridones from 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydro-pyridones. J Heterocycl Chem. 1996;33(1):103-107.

Mohammadi Ziarani G, Mousavi S, Lashgari N, Badiei A. Mesostructured SBA-15-Pr-SO3H: an efficient solid acid catalyst for one-pot and solvent-free synthesis of 3,4-dihydro-2-pyridone derivatives. J Chem Sci. 2013;125(6):1359-1364.


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