Synthesis and SAR Study of Simple Aryl Oximes and Nitrofuranyl Derivatives with Potent Activity Against Mycobacterium tuberculosis

Author(s): Cristiane França da Costa, Marcus Vinicius Nora de Souza*, Maria Cristina da Silva Lourenço, Elaine Soares Coimbra, Guilherme da Silva Lourenço Carvalho, James Wardell, Stephane Lima Calixto, Juliana da Trindade Granato

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 1 , 2020

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Abstract:

Background: Oximes and nitrofuranyl derivatives are particularly important compounds in medicinal chemistry. Thus, many researchers have been reported to possess antibacterial, antiparasitic, insecticidal and fungicidal activities.

Methods: In this work, we report the synthesis and the biological activity against Mycobacterium tuberculosis H37RV of a series of fifty aryl oximes, ArCH=N-OH, I, and eight nitrofuranyl compounds, 2-nitrofuranyl-X, II.

Results: Among the oximes, I: Ar = 2-OH-4-OH, 42, and I: Ar = 5-nitrofuranyl, 46, possessed the best activity at 3.74 and 32.0 µM, respectively. Also, 46, the nitrofuran compounds, II; X = MeO, 55, and II: X = NHCH2Ph, 58, (14.6 and 12.6 µM, respectively), exhibited excellent biological activities and were non-cytotoxic.

Conclusion: The compound 55 showed a selectivity index of 9.85. Further antibacterial tests were performed with compound 55 which was inactive against Enterococcus faecalis, Klebisiella pneumonae, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhymurium and Shigella flexneri. This study adds important information to the rational design of new lead anti-TB drugs. Structure-activity Relationship (SAR) is reported.

Keywords: Tuberculosis, aryl oximes, nitrofuranyl derivatives, Mycobacterium tuberculosis, cytotoxicity, Staphylococcus aureus.

[1]
World Health Organization. Global Report Tuberculosis 2016.http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1 (Accessed August, 15, 2018)
[2]
Cunico, W.; Gomes, C.R.B.; Ferreira, M.L.G.; Ferreira, T.G.; Cardinot, D.; de Souza, M.V.N.; Lourenço, M.C.S. Synthesis and anti-mycobacterial activity of novel amino alcohol derivatives. Eur. J. Med. Chem., 2011, 46(3), 974-978.
[http://dx.doi.org/10.1016/j.ejmech.2011.01.004] [PMID: 21295888]
[3]
Da Costa, C.F.; Pinheiro, A.C.; De Almeida, M.V.; Lourenço, M.C.S.; De Souza, M.V.N. Synthesis and antitubercular activity of novel amino acid derivatives. Chem. Biol. Drug Des., 2012, 79(2), 216-222.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01269.x] [PMID: 22078007]
[4]
Gomes, C.R.B.; Moreth, M.; Facchinetti, V.; De Souza, M.V.N.; Júnior, W.T.V.; Lourenço, M.C.S.; Cunico, W. Synthesis and Antimycobacterial activity of 2-aryl-3-(arylmethyl)-1,3-thiazolidin-4-ones. Lett. Drug Des. Discov., 2010, 7, 353-358.
[http://dx.doi.org/10.2174/157018010791163451]
[5]
Ackart, D.F.; Lindsey, E.A.; Podell, B.K.; Melander, R.J.; Basaraba, R.J.; Melander, C. Reversal of Mycobacterium tuberculosis phenotypic drug resistance by 2-aminoimidazole-based small molecules. Pathog. Dis., 2014, 70(3), 370-378.
[http://dx.doi.org/10.1111/2049-632X.12143] [PMID: 24478046]
[6]
Warner, D.F.; Koch, A.; Mizrahi, V. Diversity and disease pathogenesis in Mycobacterium tuberculosis. Trends Microbiol., 2015, 23(1), 14-21.
[http://dx.doi.org/10.1016/j.tim.2014.10.005] [PMID: 25468790]
[7]
Coluccia, A.; La Regina, G.; Barilone, N.; Lisa, M.N.; Brancale, A.; André-Leroux, G.; Alzari, P.M.; Silvestri, R. Structure-based Virtual Screening to Get New Scaffold Inhibitors of the Ser/Thr Protein Kinase PknB from Mycobacterium tuberculosis. Lett. Drug Des. Discov., 2016, 10, 1012-1018.
[http://dx.doi.org/10.2174/1570180813666160801162204]
[8]
Brigden, G.; Hewison, C.; Varaine, F. New developments in the treatment of drug-resistant tuberculosis: Clinical utility of bedaquiline and delamanid. Infect. Drug Resist., 2015, 8, 367-378.
[http://dx.doi.org/10.2147/IDR.S68351] [PMID: 26586956]
[9]
Facchinetti, V.; Souza, M.V.N.; Nery, A.C.S.; Calixto, S.L.; Granato, J.T.; Coimbra, E.S.C.; Lourenço, M.C.S.; Gomes, C.R.B.; Vasconcelos, T.R.A. Synthetic aspects and first-time assessment of 2-amino-1,3-selenazoles against Mycobacterium tuberculosis. Lett. Drug Des. Discov., 2018, 15, 1224-1229.
[http://dx.doi.org/10.2174/1570180815666180209153925]
[10]
Tangallapally, R.P.; Yendapally, R.; Daniels, A.J.; Lee, R.E.B.; Lee, R.E. Nitrofurans as novel anti-tuberculosis agents: Identification, development and evaluation. Curr. Top. Med. Chem., 2007, 7(5), 509-526.
[http://dx.doi.org/10.2174/156802607780059772] [PMID: 17346196]
[11]
Souza, J.L.S.; Nedel, F.; Ritter, M.; Carvalho, P.H.; Pereira, C.M.; Lund, R.G. Antifungal susceptibility, exoenzyme production and cytotoxicity of novel oximes against Candida. Mycopathologia, 2013, 176(3-4), 201-210.
[http://dx.doi.org/10.1007/s11046-013-9675-7] [PMID: 23824511]
[12]
Ma, J.; Ma, M.; Sun, L.; Zeng, Z.; Jiang, H. Synthesis, herbicidal evaluation, and structure-activity relationship of benzophenone oxime ether derivatives. J. Chem., 2015, 2015, 1-8.
[http://dx.doi.org/10.1155/2015/435219]
[13]
Rakesh, D.B.; Bruhn, M.; Madhura, R.B. Maddox, Lee, Trivedi, A.; Yang, L.; Scherman, M.S.; Gilliland, J.C.; Gruppo, V.; McNeil, M.R.; Lenaerts, A.J.; Meibohm, B.; Lee, R.E. Antitubercular nitrofuran isoxazolines with improved pharmacokinetic properties. Bioorg. Med. Chem., 2012, 20, 6063-6072.
[14]
Tawari, N.R.; Degani, M.S.; Chem, T. Pharmacophore modeling and density functional theory analysis for a series of nitroimidazole compounds with antitubercular activity. Chem. Biol. Drug Des., 2011, 78(3), 408-417.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01161.x] [PMID: 21689377]
[15]
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-Baltork, V.; Moosavifa, M. Host (nanocavity of dealuminated zeolite Y)–guest (12-molybdophosphoric acid) nanocomposite material: An efficient and reusable catalyst for oximation of aldehydes. Appl. Catal. A Gen., 2009, 2, 157-163.
[http://dx.doi.org/10.1016/j.apcata.2009.02.008]
[16]
Tavares, A.; Ritter, O.M.S.; Vasconcelos, U.B.; Arruda, B.C.; Schrader, A.; Schneider, P.H.; Merlo, A.A. Synthesis of liquid-crystalline 3,5-diarylisoxazolines. Liq. Cryst., 2010, 2, 159-169.
[http://dx.doi.org/10.1080/02678290903432098]
[17]
Popelis, J.; Liepins, E.; Stradins, J. Proton and carbon-13 NMR of 2-substituted 5-nitrofurans and conformation of chemotherapeutic preparations of the 5-nitrofuran series. Khim. Geterotsikl., 1980, 2, 167-176.
[http://dx.doi.org/10.1002/chin.198025056]
[18]
Younus Wani, M.; Athar, F.; Salauddin, A.; Mohan Agarwal, S.; Azam, A.; Choi, I.; Roouf Bhat, A. Novel terpene based 1,4,2-dioxazoles: Synthesis, characterization, molecular properties and screening against Entamoeba histolytica. Eur. J. Med. Chem., 2011, 46(9), 4742-4752.
[http://dx.doi.org/10.1016/j.ejmech.2011.06.005] [PMID: 21715066]
[19]
Dixon, S.M.; Milinkevich, K.A.; Fujii, J.; Liu, R.; Yao, N.; Lam, K.S.; Kurth, M.J. A spiroisoxazolinoproline-based amino acid scaffold for solid phase and one-bead-one-compound library synthesis. J. Comb. Chem., 2007, 9(1), 143-157.
[http://dx.doi.org/10.1021/cc060090p] [PMID: 17206843]
[20]
Liu, Y.; Cai, B.; Li, Y.; Song, H.; Huang, R.; Wang, Q. Synthesis, crystal structure, and biological activities of 2-cyanoacrylates containing furan or tetrahydrofuran moieties. J. Agric. Food Chem., 2007, 55(8), 3011-3017.
[http://dx.doi.org/10.1021/jf0636519] [PMID: 17381123]
[21]
Bianco, A.; Brufani, M.; Dri, D.A.; Melchioni, C.; Filocamo, L. Design and synthesis of a new furanosic sialymimetic as a potential influenza neuraminidase viral inhibitor. Lett. Org. Chem., 2005, 2, 83-88.
[http://dx.doi.org/10.2174/1570178053400207]
[22]
Zhou, L.; Stewart, G.; Rideau, E.; Westwood, N.J.; Smith, T.K. A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro. J. Med. Chem., 2013, 56(3), 796-806.
[http://dx.doi.org/10.1021/jm301215e] [PMID: 23281892]
[23]
Franzblau, S.G.; Witzig, R.S.; McLaughlin, J.C.; Torres, P.; Madico, G.; Hernandez, A.; Degnan, M.T.; Cook, M.B.; Quenzer, V.K.; Ferguson, R.M.; Gilman, R.H. Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay. J. Clin. Microbiol., 1998, 36(2), 362-366.
[PMID: 9466742]
[24]
Vanitha, J.D.; Paramasivan, C.N. Evaluation of microplate Alamar blue assay for drug susceptibility testing of Mycobacterium avium complex isolates. Diagn. Microbiol. Infect. Dis., 2004, 49(3), 179-182.
[http://dx.doi.org/10.1016/j.diagmicrobio.2004.04.003] [PMID: 15246507]
[25]
Reis, R.S.; Neves, I., Jr; Lourenço, S.L.S.; Fonseca, L.S.; Lourenço, M.C.S. Comparison of flow cytometric and Alamar Blue tests with the proportional method for testing susceptibility of Mycobacterium tuberculosis to rifampin and isoniazid. J. Clin. Microbiol., 2004, 42(5), 2247-2248.
[http://dx.doi.org/10.1128/JCM.42.5.2247-2248.2004] [PMID: 15131202]
[26]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[27]
Glanzmann, N.; Carmo, A.M.L.; Antinarelli, L.M.R.; Coimbra, E.S.; Costa, L.A.S.; da Silva, A.D. Synthesis, characterization, and NMR studies of 1,2,3-triazolium ionic liquids: A good perspective regarding cytotoxicity. J. Mol. Model., 2018, 24(7), 160.
[http://dx.doi.org/10.1007/s00894-018-3682-z] [PMID: 29904800]
[28]
(a) Yin, L.; Jia, J.; Zhao, G.L.; Xu, W.R.; Tang, L.D.; Wang, J.W. Design, synthesis and antibacterial activity of novel N-formylhydroxylamine derivatives as PDF inhibitors. Indian J. Chem. B, 2011, 50B, 695-703.
[http://dx.doi.org/10.1002/chin.201138076]
(b) Chang, L.K.; Shelton, B.R.; Howe, R.K. A particularly convenient preparation of benzohydroximinoyl chlorides (nitrile oxide precursors). J. Org. Chem., 1980, 45, 3916-3918.
[http://dx.doi.org/10.1021/jo01307a039]
(c) Dewan, S.K.; Singh, R. Microwave assisted stereoselective synthesis of Z-oximes in the presence of zinc sulfate in dry media. Orient. J. Chem., 2003, 19, 217-219.
(d) Edjlali, L. The regiospecific synthesis of some new 3,5-disubstituted isoxazoles. J. Chin. Chem. Soc. (Taipei), 2008, 55, 1322-1325.
[http://dx.doi.org/10.1002/jccs.200800198]
(e) Mokhtari, J.; Naimi-Jamal, M.R.; Hamzeali, H.; Dekamin, M.G.; Kaupp, G. An efficient procedure for synthesis of oximes by grinding. ChemSusChem, 2009, 2, 248-254.
[http://dx.doi.org/10.1002/cssc.200800258] [PMID: 19266517]
(f) Brady, O.L.; Jarrett, S.G. Hydrolysis of acyl halobenzaldoximes by alkalies. J. Chem. Soc., 1950, 1227-1232.
[http://dx.doi.org/10.1039/jr9500001227]
(g) Picha, J.; Cibulka, R.; Hampl, F.; Liska, F.; Parik, P.; Pytela, O. Reactivity of p-substituted benzaldoximes in the cleavage of p-nitrophenyl acetate: Kinetics and mechanism. Collect. Czech. Chem. Commun., 2004, 69, 397-413.
[http://dx.doi.org/10.1135/cccc20040397]
(h) Liu, K.C.; Shelton, B.R.; Howe, R.K. A particularly convenient preparation of benzohydroximinoyl chlorides (nitrile oxide precursors). J. Org. Chem., 1980, 45, 3916-3918.
[http://dx.doi.org/10.1021/jo01307a039]
(i)]Zhang Lh, L.; Chung, J.C.; Costello, T.D.; Valvis, I.; Ma, P.; Kauffman, S.; Ward, R. The Enantiospecific Synthesis of an Isoxazoline. A RGD Mimic Platelet GPIIb/IIIa Antagonist. J. Org. Chem., 1997, 62(8), 2466-2470.
[http://dx.doi.org/10.1021/jo9612537] [PMID: 11671583]
(j)Conduche, A. Contributions to the study of oxyureas and carbamidoximes (Contin.). Ann. Chim. Phys., 1908, 13, 1-91.
(k)Witkop, B.; Beiler, T.W. Studies on Schiff bases in connection with the mechanism of transamination. J. Am. Chem. Soc., 1954, 74, 5589-5597.
[http://dx.doi.org/10.1021/ja01651a002]
(l)Joseph, M.M.; Jacob, D.E. Reduction of polyfunctional aromatic nitro compounds using lithium aluminum hydride. Indian J. Chem. B, 2004, 43, 432-436.
[http://dx.doi.org/10.1002/chin.200422059]
(m)Vilela, G.D.; Da Rosa, R.R.; Schneider, P.H.; Schneider, I.H.; Eccher, X.J.; Merlo, A.A. Expeditious preparation of isoxazoles from Δ2-isoxazolines as advanced intermediates for functional materials. Tetrahedron Lett., 2011, 52, 6569-6572.
[http://dx.doi.org/10.1016/j.tetlet.2011.09.122]
(n)Wang, E.C.; Huang, K.; Chen, H.M.; Wu, C.C.; Lin, G.J. An efficient method for the preparation of nitriles via the dehydration of aldoximes with phthalic anhydride. J. Chin. Chem. Soc. (Taipei), 2004, 51, 619-627.
[http://dx.doi.org/10.1002/jccs.200400093]
(o)Ismail, T.; Shafi, S.; Singh, P.P.; Qazi, N.A.; Sawant, S.D.; Ali, I.; Khan, I.A.; Kumar, H.M.S.; Qazi, G.N.; Alam, M.S. Biologically active hydroxymoyl chlorides as antifungal agents. Indian J. Chem. B, 2008, 47, 740-747.
(p)Portela-Cubillo, F.; Lymer, J.; Scanlan, E.M.; Scott, J.S.; Walton, J.C. Dioxime oxalates; new iminyl radical precursors for syntheses of N-heterocycles. Tetrahedron, 2008, 64, 11908-11916.
[http://dx.doi.org/10.1016/j.tet.2008.08.112]
(q)Illescas, B.M.; Martin, N. Fullerene adducts with improved electron acceptor properties.[In Process Citation] J. Org. Chem., 2000, 65(19), 5986-5995.
[http://dx.doi.org/10.1021/jo0003753] [PMID: 10987931]
(r)Sieger, G.M.; Klein, D.X. Local anesthetics. I. Dialkylaminoalkyl ethers of benzaldoximes and benzophenone oximes. J. Org. Chem., 1957, 22, 951-954.
[http://dx.doi.org/10.1021/jo01359a026]
(s)Moghadam, M. Host (nanocavity of dealuminated zeolite Y)-guest (12-molybdophosphoric acid) nanocomposite material: An efficient and reusable catalyst for oximation of. Appl. Catal., 2009, 358, 157-163.
[http://dx.doi.org/10.1016/j.apcata.2009.02.008]
(t)Maheswara, M.V.; Siddaiah, K.; Gopalaiah, V.M.; Rao, C.V. A simple and effective glycine-catalyzed procedure for the preparation of oximes. J. Chem. Res., 2006, 6, 362-363.
[http://dx.doi.org/10.3184/030823406777946770]
(u)Meyers, C.Y. Aromatic aldehydes from benzyl alcohols via inorganic hypochlorite oxidation. J. Org. Chem., 1961, 26, 1046-1050.
[http://dx.doi.org/10.1021/jo01063a018]
(v)Wiley, R.H.; Wakefield, B.J. Infrared spectra of the nitrile N-oxides: Some new furoxans. J. Org. Chem., 1960, 25, 546-551.
(w)Gomes, L.R.; De Souza, M.V.N.; Da Costa, C.F.; Wardell, J.L.; Low, J.N. Different classical hydrogen-bonding patterns in three salicylaldoxime derivatives, 2-HO-4-XC6H3C NOH (X = Me, OH and MeO). Acta Crystallogr., 2018, E74, 1480-1485.
(x)Gomes, L.R.; De Souza, M.V.N.; Da Costa, C.F.; Wardell, J.L.; Low, J.N. Crystal structures and Hirshfeld surfaces of four methoxybenzaldehyde oxime derivatives, 2-MeO-XC6H3C NOH (X = H and 2-, 3- and 4-MeO): Different conformations and hydrogenbonding patterns. Acta Crystallogr., 2018, E74, 1553-1560.
[29]
(a) Giurg, M.; Brzaszcz, M.; Mlochowski, J. Hydroperoxide oxidation of different organic compounds catalyzed by silica-supported selenenamide. Pol. J. Chem., 2006, 80, 417-428.
[http://dx.doi.org/10.1002/chin.200629033]
(b) Kawabe, K.; Suzui, T.; Iguchi, M. Alkylated furan derivatives. II. Syntheses and antimicrobial activity of 5-chloro-N-alkyl-2-furamide and 5-nitro-N-alkyl-2-furamide. Yakugaku Zasshi, 1960, 80, 53-57.
[http://dx.doi.org/10.1248/yakushi1947.80.1_53]
(c) Farcasan, V.; Makkay, C. Furan derivatives. I. p-Substituted anilides of 5-nitro-2-furoic acid. Acad. Repub. Popular Romania, 1957, 8, 151-158.
(d) Gilman, H. Nitrofurfural and nitrofurylacrylic acid. J. Am. Chem. Soc., 1930, 52, 2550-2554.
[http://dx.doi.org/10.1021/ja01369a061]
(e) Low, J.N.; Wardell, J.L.C.F. Da Costa, Souza, M.V.N.; Gomes, L.R. Structural study of three heteroaryl oximes, heteroaryl-N=OH: Compounds forming strong C3 molecular chains. Eur. J. Chem., 2018, 9(3), 151-160.
[http://dx.doi.org/10.5155/eurjchem.9.3.151-160.1734]


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VOLUME: 17
ISSUE: 1
Year: 2020
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DOI: 10.2174/1570180816666181227115738
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