Abstract
Background: Antimicrobial resistance is a major threat to human health. So this manuscript describes the synthesis of five different 3,5-disubstituted 4,5-dihydroisoxazoles with antimicrobial activity.
Methods: They were obtained from nitrile oxide cycloaddition derived from 2-furaldehyde and 5- nitro-2-furaldehyde to different dipolarophiles (acrylamide, ethyl acrylate and styrene). All heterocycles were isolated (30-50 %) and characterized by FTIR, MS, 1H and 13C NMR, as they were also evaluated against Gram-positive and Gram-negative bacteria.
Results and Conclusion: All products showed bioactivity against all bacteria, however, the heterocycle 3-(5-nitro-2-furanyl)-5-carboxylamide-4,5-dihydroisoxazole (6b) presented the lowest value for the minimum inhibition concentration (MIC - 14 µg/mL).
Keywords: Cycloaddition, dihydroisoxazole, nitrile oxide, antimicrobial, bioactivity, furaldehyde.
Graphical Abstract
[1]
Luepke, K.H.; Juda, K.J.; Boucher, H.; Russo, R.L. Bonney, M.W.; Hunt, T.D.; Morh III, J.F. Past, present, and limited antibiotic pipeline, and societal implications. Pharmacotherapy, 2017, 37(1), 71-84.
[2]
Bano, S.; Alam, M.S.; Javed, K.; Dudeja, M.; Das, A.K.; Dhulap, A. Synthesis, biological evaluation and molecular docking of some substituted pyrazolines and isoxazolines as potential antimicrobial agents. Eur. J. Med. Chem., 2015, 95, 96-103.
[3]
Mijac, V.; Opavski, N.; Markovic, M.; Gagic, I.; Vasiljevic, Z.; Sipetic, T. Trends in macrolide resistance of respiratory tract pathogens in the pediatric population in Serbia from 2004 to 2009. Epidemiol. Infect., 2015, 143(3), 648-652.
[4]
Tavares, F.S.; Paula, F.R.; Serrano, S.P. Aspects of bioactivity and toxicity of nitrocompounds. Quim. Nova, 2009, 32, 1013-1020.
[5]
Shi, L.; Hu, R.; Wei, Y.; Liang, Y.; Yang, Z.; Ke, S. Anthranilic acid-based diamides derivatives incorporating aryl-isoxazoline pharmacophore as potential anticancer agents: Design, synthesis and biological evaluation. Eur. J. Med. Chem., 2012, 54, 549-556.
[6]
Kumar, A.B.V.K.; Sankar, A.U.R.; Kim, S.H. A simple, efficient one-pot synthesis of 2-isoxazoline derivatives and their antimicrobial activity. J. Het. Chem., 2014, 51, E146-E151.
[7]
Jakubiec, D.; Przypis, L.; Suwinski, J.W.; Walczak, K.Z. Syntheis of 5-hetaryluracil derivatives via 1,3-dipolar cycloaddition reaction. Arkivoc, 2017, 2, 149-161.
[8]
Murugasu-Oei, B.; Dick, T. Bactericidal activity of nitrofurans against growing and dormant Mycobacterium bovis BCG. J. Antimicrob. Chemother., 2000, 46, 917-919.
[9]
Tangallapally, R.P.; Sun, D. Rakesh; Budha, N.; Lee, R.E.B.; Lenaerts, A.J.M.; Meibohm, B.; Lee, R.E. Discovery of novel isoxazolines as anti-tuberculosis agents. Bioorg. Med. Chem. Lett., 2007, 17, 6638-6642.
[10]
Sridhara, A.M.; Reddy, K.R.V.; Keshavayya, J.; Ambika, D.M.S.; Gopinath, V.S.; Bose, P.; Goud, K.; Peethambar, S.K. Synthesis, antimicrobial and cytotoxicity studies of some novel modified strobilurin derivatives. J. Braz. Chem. Soc., 2011, 5, 849-856.
[11]
Kumar, K.A.; Lokeshwari, D.M.; Kumar, G.V. Evaluation and studies on the structural impact of substituted 4,5-dihydroisoxazoles on their biological activities. Int. J. Pharma. Sci. Drug Res., 2012, 4(4), 236-239.
[12]
Zhang, Y.K.; Plattner, J.J.; Zhou, Y.; Xu, M.; Cao, J.; Wu, Q. Novel synthesis of isoxazoline indolizine amides for potential application to tropical diseases. Tetrahedron Lett., 2014, 55, 1936-1938.
[13]
Kaur, K.; Kumar, V.; Sharma, A.K.; Gupta, G.K. Isoxazoline containing natural products as anticancer agents: A review. Eur. J. Med. Chem., 2014, 77, 121-133.
[14]
Gantala, M.; Ghanta, J.R.; Mittapellic, V. A facile synthesis and in vitro biological evaluation of a series of substituted benzofurans as antitubercular agents. World J. Pharm. Res., 2017, 6(2), 1392-1411.
[15]
Zaitseva, J.; Granik, V.; Belik, A.; Koksharova, O.; Khmel, I. Effects of nitrofurans and NO generators on biofilm formation by Pseudomonas aeruginosa PA01 and Burkholderia cenocepacia 370. Res. Microbiol., 2009, 160, 353-357.
[16]
Afraj, S.N.; Nuzlia, C.; Chen, C.; Lee, G.H. Multicomponent coupling reaction and intramolecular nitrile oxide-alkyne cycloaddition towards isoxazolo[3,4]-pyrrolizines. Asian J. Org. Chem., 2016, 5(8), 1015-1026.
[17]
Mótyán, G.; Baji, A.; Zupk, I.; Frank, E. Regio- and stereoselective synthesis of pregnane-fused isoxazolines by nitril-oxide/alkene 1,3- dipolar cycloaddition and an evaluation of their cell-growth inhibitory effect in vitro. J. Mol. Struct., 2016, 1110, 143-149.
[18]
Kumar, R.S.; Ramar, A.; Perumal, S.; Almansour, A.I.; Arumugam, N.; Ali, M.A. Three-component synthesis and 1,3-dipolar cycloaddition of highly functionalized pyrans with nitrile oxides: Easy access to 1,2,4-oxadiazoles. Synth. Commun., 2013, 43(20), 2763-2772.
[19]
Huisgen, R. On the mechanism of 1,3-dipolar cycloadditions. A reply. J. Org. Chem., 1968, 33(6), 2291-2297.
[20]
Domingo, L.R.; Picher, M.T.; Arroyo, P.; Sáez, J.A. 1,3-Dipolar cycloadditions of electrophilically activated benzonitrile N-oxides. Polar cycloaddition versus oxime formation. J. Org. Chem., 2006, 71(25), 9320-9330.
[21]
Jasiński, R. A stepwise, zwitterionic mechanism for the 1,3-dipolar cycloaddition between (Z)-C-4-methoxyphenyl-N-phenylnitrone and gem-chloronitroethene catalysed by 1-butyl-3-methylimidazolium ionic liquid cations. Tetrahedron Lett., 2015, 56(3), 532-535.
[22]
Jasiński, R. Competition between one-step and two-step mechanism in polar [3+2] cycloadditions of (Z)-C-(3,4,5-trimethoxyphenyl)-N-methyl-nitrone with (Z)-2-EWG-1-bromo-1-nitroethenes. Comput. Theor. Chem., 2018, 1125, 77-85.
[23]
Jasiński, R. In the searching for zwitterionic intermediates on reaction paths of [3+2] cycloaddition reactions between 2,2,4,4- tetramethyl-3-thiocyclobutanone S-methylide and polymerizable olefins. RSC Adv, 2015, 5, 101045-101048.
[24]
Mlostoń, G.; Urbaniaka, K.; Lindenb, A.; Heimgartner, H. Selenophen-2-yl-substituted thiocarbonyl ylides - at the borderline of dipolar and biradical reactivity. Helv. Chim. Acta, 2015, 98, 453-461.
[25]
Jasiński, R. Nitroacetylene as dipolarophile in [2 + 3] cycloaddition reactions with allenyl-type three-atom components: DFT computational study. Monatsh. Chem., 2015, 146, 591-599.
[26]
Jasiński, R.; Ziółkowska, M.; Demchuk, O.M.; Maziarka, A. Regio- and stereoselectivity of polar [2+3] cycloaddition reactions between (Z)-C-(3,4,5-trimethoxyphenyl)-N-methylnitrone and selected (E)-2-substituted nitroethenes. Cent. Eur. J. Chem., 2014, 12(5), 586-593.
[27]
Weidner-Wells, M.A.; Werblood, H.M.; Goldschmidt, R.; Bush, K.; Foleno, B.D.; Hilliard, J.J.; Melton, J.; Wira, E.; Macielag, M.J. The synthesis and antimicrobial evaluation of a new series of isoxazolinyl oxazolidinones. Bioorg. Med. Chem. Lett., 2004, 14, 3069-3072.
[28]
Vitale, P.; Scilimati, A. Recent Developments in the Chemistry of 3-Arylisoxazoles and 3-Aryl-2-isoxazolines. Adv. Heterocycl. Chem., 2017, 122, 1-41.
[29]
Shah, T.; Desai, V. Synthesis and antibacterial studies of some novel isoxazoline derivatives. J. Serb. Chem. Soc., 2007, 72, 443-449.
[30]
Babu, M.S.; Rai, K.M.L. Synthesis of podophyllotoxin and its derivatives via NiCl2/NaBH4 reduction of isoxazoline ring. Asian J. Chem., 2013, 25, 9555-9557.
[31]
Zhang, P.; Li, C.; Yang, H.; Wei, H.; Xia, Z.; Ma, D.; Chen, H.; Wang, K.; Li, X. A convenient synthesis of novel aza-Cdisaccharide analogues. Carbohydr. Res., 2014, 398, 36-39.
[32]
Pirrung, M.C.; Tumey, L.N.; Raetz, C.R.H.; Jackman, J.E.
Snehalatha, K.; McClerren, A.L. Fierke, C.A.; Gantt, Rusche, K.M. Inhibition of the antibacterial target UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC): Isoxazoline zinc amidase inhibitors bearing diverse metal binding groups. J. Med. Chem., 2002, 45, 4359-4370.
Snehalatha, K.; McClerren, A.L. Fierke, C.A.; Gantt, Rusche, K.M. Inhibition of the antibacterial target UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC): Isoxazoline zinc amidase inhibitors bearing diverse metal binding groups. J. Med. Chem., 2002, 45, 4359-4370.
[33]
Tangallapally, R.P.; Yendapally, R.; Daniels, A.J.; Lee, R.E.B.; Lee, R.E. Nitrofurans as novel antituberculosis agents: Identification, development and evaluation. Curr. Med. Chem., 2007, 7, 509-526.
[34]
Rodrigues, R.C.; Aguiar, A.P. A simple and efficient method for the synthesis of nitrile oxide from aldoxime using trichloroisocyanuric acid. Synthetic. Commun., 2001, 31, 3075-3080.
[35]
Aguiar, A.P.; Molina, C.T. Synthesis of new 4,5-dihydroisoxazoles with potential anti-inflammatory activity. Heterocycl. Commun., 2003, 9, 535-538.
[36]
Sasaki, T.; Yoshioka, T. Studies on Heteroaromaticity. XIX Direct 1,3-dipolar cycloaddition of fur- and 5-nitro-2-furhydroxamoyl chlorides with olefinic and acetylenic compounds. Bull. Chem. Soc., 1967, 40, 2604-2607.
[37]
National Committee for Clinical Laboratory Standards (NCCLS). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard M7−A6, 6th ed., Wayne, Pa, 2003.
[38]
Rodrigues, G.C.; Feijó, D.F.; Bozza, M.T.; Pan, P.; Vullo, D.; Parkkila, S.; Supuran, C.T.; Capasso, C.; Aguiar, A.P.; Vermelho, A.B. Design, synthesis, and evaluation of hydroxamic acid derivatives as promising agents for the management of Chagas disease. J. Med. Chem., 2014, 57, 298-308.
[39]
Silva, B.V.; Esteves, P.M.; Pinto, A.C. Chlorination of isatins with trichloroisocyanuric acid. J. Braz. Chem. Soc., 2011, 22, 257-263.
[40]
Zagozda, M.; Plenkiewicz, J. Optically active nitrile oxides: Synthesis and 1,3 dipolar cycloaddition reactions. Tetrahedron. Asymetry, 2007, 18, 1457-1464.
[41]
Rakesh, Sun. D.; Lee, R.B.; Tangallapally, R.P.; Lee, R.E. Synthesis, optimization and structure-activity relationships of 3,5-disubstituted isoxazolines as new anti-tuberculosis. Eur. J. Med. Chem., 2009, 44, 460-472.
[42]
Silverstein, R.M.F.; Webster, X.D.; Kiemle, J. Spectrometric Identification of Organic Compounds, 7th ed; John Wiley & Sons Inc.: New York, 2005.
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