Synthesis and Evaluation of the in vitro Antimicrobial Activity of Triazoles, Morpholines and Thiosemicarbazones

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Abstract

Background: Microbial infections is a global public health problem. The aim of this work was to synthesize and evaluate the antimicrobial activity of novel triazoles, morpholines and thiosemicarbazones.

Methods: Compounds were synthesized using 2,4-Dihydroxyacetophenone and 4-hydroxybenzaldehyde as starting materials. The antimicrobial activity of these compounds against bacteria and yeast was evaluated by the broth microdilution method.

Results: The proposed route for synthesis gave high to moderate yields, moreover these compounds were successfully characterized by 1H NMR, 13C NMR and LC-MS. Antimicrobial testing indicated that the thiosemicarbazone and morphine derivatives had the best antimicrobial activity against the microorganisms tested with minimum inhibitory concentrations (MIC) between 0.29 and 5.30 µM. Thiosemicarbazone derivative (12) was able to inhibit the growth of C. tropicalis, with minimum fungicidal concentration (MFC) of 0.55 µM. In addition, this compound was active against E. coli, S. aureus and S. epidermidis, with MIC values ranging from 0.29 to 1.11 µM. Moreover, the morpholine derivative (15) had an MIC value of 0.83 µM against C. albicans and E. coli.

Conclusion: We have efficiently synthesized a series of eleven novel triazoles, thiosemicarbazones and morpholine derivatives using 2,4-Dihydroxyacetophenone and 4-hydroxybenzaldehyde as starting materials. Thiosemicarbazone derivative (12) showed promising antifungal and antibacterial activity and these findings suggest that this compound can be used as scaffolds to design new antimicrobial drugs.

Keywords: Antifungal, antibacterial, Bacterial resistance, triazoles, morpholines, thiosemicarbazones.

Graphical Abstract

[1]
Ertan-Bolelli, T.; Yildiz, İ.; Ozgen-Ozgacar, S. Synthesis, molecular docking and antimicrobial evaluation of novel benzoxazole derivatives. Med. Chem. Res., 2016, 25(4), 553-567.
[2]
Regiel-Futyra, A.; Dabrowski, J.M.; Mazuryk, O.; S’piewak, A.K.; Pucelik, B.; Brindell, M.; Stochel, G. Bioinorganic antimicrobial strategies in the resistance era. Coord. Chem. Rev., 2017, 351, 76-117.
[3]
Golkar, Z.; Bagasra, O.; Pace, D.G. Bacteriophage therapy: a potential solution for the antibiotic resistance crisis. J. Infect. Dev. Ctries., 2014, 8(2), 129-136.
[4]
Gales, A.C.; Jones, R.N.; Sader, H.S. Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: results from the SENTRY Antimicrobial Surveillance Program (2006-09). J. Antimicrob. Chemother., 2011, 66(9), 2070-2074.
[5]
Marra, A.R.; Camargo, L.F.; Pignatari, A.C.; Sukiennik, T.; Behar, P.R.; Medeiros, E.A.; Ribeiro, J.; Girao, E.; Correa, L.; Guerra, C.; Brites, C.; Pereira, C.A.; Carneiro, I.; Reis, M.; de Souza, M.A.; Tranchesi, R.; Barata, C.U.; Edmond, M.B.; Brazilian, S.S.G. Nosocomial bloodstream infections in Brazilian hospitals: analysis of 2,563 cases from a prospective nationwide surveillance study. J. Clin. Microbiol., 2011, 49(5), 1866-1871.
[6]
Rosenthal, V.D.; Al-Abdely, H.M.; El-Kholy, A.A.; AlKhawaja, S.A.; Leblebicioglu, H.; Mehta, Y.; Rai, V.; Hung, N.V.; Kanj, S.S.; Salama, M.F.; Salgado-Yepez, E.; Elahi, N.; Morfin Otero, R.; Apisarnthanarak, A.; De Carvalho, B.M.; Ider, B.E.; Fisher, D.; Buenaflor, M.C.; Petrov, M.M.; Quesada-Mora, A.M.; Zand, F.; Gurskis, V.; Anguseva, T.; Ikram, A.; Aguilar de Moros, D.; Duszynska, W.; Mejia, N.; Horhat, F.G.; Belskiy, V.; Mioljevic, V.; Di Silvestre, G.; Furova, K.; Ramos-Ortiz, G.Y.; Gamar Elanbya, M.O.; Satari, H.I.; Gupta, U.; Dendane, T.; Raka, L.; Guanche-Garcell, H.; Hu, B.; Padgett, D.; Jayatilleke, K.; Ben Jaballah, N.; Apostolopoulou, E.; Prudencio Leon, W.E.; Sepulveda-Chavez, A.; Telechea, H.M.; Trotter, A.; Alvarez-Moreno, C.; Kushner-Davalos, L. International nosocomial infection control consortium report, data summary of 50 countries for 2010-2015: Device-associated module. Am. J. Infect. Control, 2016, 44(12), 1495-1504.
[7]
World Health Organization (WHO). Antimicrobial resistance: global report on surveillance, 2014.who.int/mediacentre/news/ releases/2014/amrreport/en/# (Accessed May 22, 2017)
[8]
Gould, I.M.; Bal, A.M. New antibiotic agents in the pipeline and how they can help overcome microbial resistance. Virulence, 2013, 4(2), 185-191.
[9]
Trubiano, J.A.; Padiglione, A.A. Nosocomial infections in the intensive care unit. Anaesth. Intensive Care, 2015, 16(12), 598-602.
[10]
Schelenz, S. Management of candidiasis in the intensive care unit. J. Antimicrob. Chemother., 2008, 61(Suppl. 1), i31-i34.
[11]
Khan, H.A.; Baig, F.K.; Mehboob, R. Nosocomial infections: Epidemiology, prevention, control and surveillance. Asian Pac. J. Trop. Biomed., 2017, 7(5), 478-482.
[12]
Lemke, T.L.; Williams, D.A.; Roche, V.F.; Zito, S.W. Foye’s principles of medicinal chemistry, 6th ed; Lippincott Williams & Wilkins: New York, 2008.
[13]
Tenório, R.P.; Góes, A.J.; de Lima, J.G.; de Faria, A.R.; Alves, A.J.; de Aquino, T.M. Tiossemicarbazonas: métodos de obtenção, aplicações sintéticas e importância biológica. Quim. Nova, 2005, 28(6), 1030-1037.
[14]
Pandiarajan, D.; Ramesh, R.; Liu, Y. Suresh, R. Palladium(II) thiosemicarbazone-catalyzed Suzuki–Miyaura cross-coupling reactions of aryl halides. Inorg. Chem. Commun., 2013, 33, 33-37.
[15]
Ramdass, A.; Sathish, V.; Velayudham, M.; Thanasekaran, P.; Lu, K.; Rajagopal, S. Monometallic rhenium(I) complexes as sensor for anions. Inorg. Chem. Commun., 2013, 35, 186-191.
[16]
Matesanz, A.I.; Tapia, S.; Souza, P. First 3,5-diacetyl-1,2,4-triazol derived mono(thiosemicarbazone) and its palladium and platinum complexes: Synthesis, structure and biological properties. Inor-ganica Chim. Acta, 2016, 445, 62-69.
[17]
Stefani, C.; Al-Eisawi, Z.; Jansson, P.J.; Kalinowski, D.S.
Richardson, D.R. Identification of differential anti-neoplastic activity of copper bis(thiosemicarbazones) that is mediated by intracellular reactive oxygen species generation and lysosomal membrane permeabilization. J. Inorg. Biochem., 2015, 152, 20-37.
[18]
Haribabu, J.; Subhashree, G.R.; Saranya, S.; Gomathi, K.; Karvembu, R.; Gayathri, D. Isatin based thiosemicarbazone derivatives as potential bioactive agents: Anti-oxidant and molecular docking studies. J. Mol. Struct., 2016, 1110, 185-195.
[19]
Rodriguez-Arguelles, M.C.; Touron-Touceda, P.; Cao, R.; Garcia-Deibe, A.M.; Pelagatti, P.; Pelizzi, C.; Zani, F. Complexes of 2-acetyl-gamma-butyrolactone and 2-furancarbaldehyde thiosemicarbazones: antibacterial and antifungal activity. J. Inorg. Biochem., 2009, 103(1), 35-42.
[20]
Parrilha, G.L.; da Silva, J.G.; Gouveia, L.F.; Gasparoto, A.K.; Dias, R.P.; Rocha, W.R.; Santos, D.A.; Speziali, N.L.; Beraldo, H. Pyridine-derived thiosemicarbazones and their tin(IV) complexes with antifungal activity against Candida spp. Eur. J. Med. Chem., 2011, 46(5), 1473-1482.
[21]
Ilies, D.C.; Pahontu, E.; Shova, S.; Georgescu, R.; Stanica, N.; Olar, R.; Gulea, A.; Rosu, T. Synthesis, characterization, crystal structure and antimicrobial activity of copper(II) complexes with a thiosemicarbazone derived from 3-formyl-6-methylchromone. Polyhedron, 2014, 81, 123-131.
[22]
Senwar, K.R.; Sharma, P.; Reddy, T.S.; Jeengar, M.K.; Nayak, V.L.; Naidu, V.G.; Kamal, A.; Shankaraiah, N. Spirooxindole-derived morpholine-fused-1,2,3-triazoles: Design, synthesis, cytotoxicity and apoptosis inducing studies. Eur. J. Med. Chem., 2015, 102, 413-424.
[23]
Dhahagani, K.; Mathan Kumar, S.; Chakkaravarthi, G.; Anitha, K.; Rajesh, J.; Ramu, A.; Rajagopal, G. Synthesis and spectral characterization of Schiff base complexes of Cu(II), Co(II), Zn(II) and VO(IV) containing 4-(4-aminophenyl)morpholine derivatives: antimicrobial evaluation and anticancer studies. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2014, 117, 87-94.
[24]
Karad, S.C.; Purohit, V.B.; Raval, D.K. Design, synthesis and characterization of fluoro substituted novel pyrazolylpyrazolines scaffold and their pharmacological screening. Eur. J. Med. Chem., 2014, 84, 51-58.
[25]
Smelcerovic, A.; Rangelov, M.; Smelcerovic, Z.; Veljkovic, A.; Cherneva, E.; Yancheva, D.; Nikolic, G.M.; Petronijevic, Z.; Kocic, G. Two 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones as new non-purine xanthine oxidase inhibitors and anti-inflammatory agents. Food Chem. Toxicol., 2013, 55, 493-497.
[26]
Ladopoulou, E.M.; Matralis, A.N.; Nikitakis, A.; Kourounakis, A.P. Antihyperlipidemic morpholine derivatives with antioxidant activity: An investigation of the aromatic substitution. Bioorg. Med. Chem., 2015, 23(21), 7015-7023.
[27]
Karad, S.C.; Purohit, V.B.; Thakor, P.; Thakkar, V.R.; Raval, D.K. Novel morpholinoquinoline nucleus clubbed with pyrazoline scaffolds: Synthesis, antibacterial, antitubercular and antimalarial activities. Eur. J. Med. Chem., 2016, 112, 270-279.
[28]
Kumbhare, R.M.; Dadmal, T.L.; Pamanji, R.; Kosurkar, U.B.; Velatooru, L.R.; Appalanaidu, K.; Khageswara Rao, Y.; Venkateswara Rao, J. Synthesis of novel fluoro 1,2,3-triazole tagged amino bis(benzothiazole) derivatives, their antimicrobial and anticancer activity. Med. Chem. Res., 2014, 23(10), 4404-4413.
[29]
Mir, F.; Shafi, S.; Zaman, M.S.; Kalia, N.P.; Rajput, V.S.; Mulakayala, C.; Mulakayala, N.; Khan, I.A.; Alam, M.S. Sulfur rich 2-mercaptobenzothiazole and 1,2,3-triazole conjugates as novel antitubercular agents. Eur. J. Med. Chem., 2014, 76, 274-283.
[30]
Kumar, K.; Pradines, B.; Madamet, M.; Amalvict, R.; Kumar, V. 1H-1,2,3-triazole tethered mono- and bis-ferrocenylchalcone-beta-lactam conjugates: synthesis and antimalarial evaluation. Eur. J. Med. Chem., 2014, 86, 113-121.
[31]
Kaushik, C.P.; Lal, K.; Kumar, A.; Kumar, S. Synthesis and biological evaluation of amino acid-linked 1,2,3-bistriazole conjugates as potential antimicrobial agents. Med. Chem. Res., 2014, 23(6), 2995-3004.
[32]
Still, W.C.; Kahn, M.; Mitra, A. Rapid chromatographic technique for preparative separations with moderate resolution. J. Org. Chem., 1978, 43(14), 2923-2925.
[33]
Clinical and Laboratory Standards Institute (CLSI) Reference method for broth dilution antifungal susceptibility testing of yeast; approved Standard M27-A3, 3rd ed; Clinical and Laboratory Standarts Institute: Pennsylvania, 2008.
[34]
Teinkela, J.E.M.; Noundod, X.S.; Fannang, S.; Meyer, F.; Vardamides, J.C.; Mpondo, E.M.; Krause, R.W.M.; Azebaze, A.G.B.; Nguedia, J.C.A. In vitro antimicrobial activity of the methanol extract and compoundsfrom the wood of Ficus elastic Roxb. ex Hornem aerial roots. S. African . J. Bot., 2017, 111, 302-306.
[35]
Duarte, M.C.; Figueira, G.M.; Sartoratto, A.; Rehder, V.L.; Delarmelina, C. Anti-Candida activity of Brazilian medicinal plants. J. Ethnopharmacol., 2005, 97(2), 305-311.
[36]
Clinical and Laboratory Standards Institute (CSLI) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically; Approved Standard-NCCLS. 6th ed.; CLSI document M7-A6:Pennsylvania. , 2012.
[37]
Guo, Z.; Li, Q.; Wang, G.; Dong, F.; Zhou, H.; Zhang, J. Synthesis, characterization, and antifungal activity of novel inulin derivatives with chlorinated benzene. Carbohydr. Polym., 2014, 99, 469-473.
[38]
Mbaveng, A.T.; Sandjo, L.P.; Tankeo, S.B.; Ndifor, A.R.; Pantaleon, A.; Nagdjui, B.T.; Kuete, V. Antibacterial activity of nineteen selected natural products against multi-drug resistant Gram-negative phenotypes. Springerplus, 2015, 4, 823.
[39]
Sander, T.; Freyss, J.; Korff, M.V.; Rufener, C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model., 2015, 55(2), 460-473.
[40]
Andrade, J.T.; Santos, F.R.S.; Lima, W.G.; Sousa, C.D.F.; Oliveira, L.S.F.M.; Ribeiro, R.I.M.A.; Gomes, A.J.P.S.; Araújo, M.G.F.; Villar, J.A.F.P.; Ferreira, M.S. Design, synthesis, biological activity and structure-activity relationship studies of chalcone derivatives as potential anti-Candida agents. J. Antibiot., 2018.
[http://dx.doi.org/10.1038/s41429-018-0048-9]
[41]
Cooper, S.R. Resacetophenone. Org. Synth., 1941, 21, 103.
[42]
Da Silva, G.D.; Da Silva, M.G.; Souza, E.M.; Barizon, A.; Simoes, S.C.; Varotti, F.P.; Barbosa, L.A.; Viana, G.H.; Villar, J.A.F.P. Design and synthesis of new chalcones substituted with azide/triazole groups and analysis of their cytotoxicity towards HeLa cells. Molecules, 2012, 17, 10331-10343.
[43]
Kothavade, R.J.; Kura, M.M.; Valand, A.G.; Panthaki, M.H. Candida tropicalis: its prevalence, pathogenicity and increasing resistance to fluconazole. J. Med. Microbiol., 2010, 59(8), 873-880.
[44]
Pfaller, M.A.; Moet, G.J.; Messer, S.A.; Jones, R.N.; Castanheira, M. Candida Bloodstream Infections: Comparison of Species Distributions and Antifungal Resistance Patterns in Community-Onset and Nosocomial Isolates in the SENTRY Antimicrobial Surveillance Program, 2008-2009. Antimicrob. Agents Chemother., 2011, 55(2), 561-566.
[45]
Silva, S.; Negri, M.; Henriques, M.; Oliveira, R.; Williams, D.W.; Azeredo, J. Candida glabrata, Candida parapsilosis and Candida tropicalis: Biology, epidemiology, pathogenicity and antifungal resistance. FEMS Microbiol. Rev., 2012, 36(2), 288-305.
[46]
Marchi, E.; Furi, L.; Arioli, S.; Morrissey, I.; Di Lorenzo, V.; Mora, D.; Giovannetti, L.; Oggioni, M.R.; Viti, C. Novel insight into antimicrobial resistance and sensitivity phenotypes associated to qac and norA genotypes in Staphylococcus aureus. Microbiol. Res., 2015, 170, 184-194.
[47]
World Health Organization (WHO). List of bacteria for which new antibiotics are urgently needed, 2017.http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/ (Accessed April 8, 2018)
[48]
Souza, M.A.; Johann, S.; Lima, L.A.; Campos, F.F.; Mendes, I.C.; Beraldo, H.; Souza-Fagundes, E.M.; Cisalpino, P.S.; Rosa, C.A.; Alves, T.M.; de Sa, N.P.; Zani, C.L. The antimicrobial activity of lapachol and its thiosemicarbazone and semicarbazone derivatives. Mem. Inst. Oswaldo Cruz, 2013, 108(3), 342-351.
[49]
Oliveira, M.T.A.; Teixeira, A.M.R.; Cassiano, C.J.M.; Sena, Jr , D.M.; Coutinho, H.D.M.; Menezes, I.R.A.; Figueredo, F.G.; Silva, L.E.; Toledo, T.A.; Bento, R.R.F. Modulation of the antibiotic activity against multidrug resistant strains of 4-(phenylsulfonyl) morpholine. Saudi J. Biol. Sci., 2016, 23(1), 34-38.
[50]
Kant, R.; Singh, V.; Nath, G.; Awasthi, S.K.; Agarwal, A. Design, synthesis and biological evaluation of ciprofloxacin tethered bis-1,2,3-triazole conjugates as potent antibacterial agents. Eur. J. Med. Chem., 2016, 124, 218-228.
[51]
Liu, J.; Yi, W.; Wan, Y.; Ma, L.; Song, H. 1-(1-Arylethylidene) thiosemicarbazide derivatives: A new class of tyrosinase inhibitors. Bioorg. Med. Chem., 2008, 16, 1096-1102.
[52]
Zhenga, J.; Zhanga, R.; Chena, Y.; Yea, X.; Chena, Q.; Shenb, D.; Wanga, Q. Synthesis of caffeic acid ester morpholines and their activation effects on tyrosinase. Proc Biochem., 2017, 62, 91-98.
[53]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-2.