Synthesis and Evaluation of Antifungal and Antitrypanosomastid Activities of Symmetrical 1,4-Disubstituted-1,2,3-Bistriazoles Obtained by CuAAC Conditions

Author(s): Mauricio M. Victor*, Ravir R. Farias, Danielle L. da Silva, Paulo H.F. do Carmo, Maria A. de Resende-Stoianoff, Cláudio Viegas, Patrícia F. Espuri, Marcos J. Marques.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: The trypanosomatids, such as the protozoan Leishmania spp., have a demand by ergosterol, which is not present in the membrane from mammal cells. The suppression of the synthesis of ergosterol would be a new target of compounds with leishmanicidal activity, and bistriazole has shown trypanocidal activity by this mechanism. The incidence of fungal infections has increased at an alarming rate over the last decades. This is related both to the growing population of immune-compromised individuals and to the emergence of strains that are resistant to available antifungals. Therefore, there is a challenge for the search of potential new antifungal agents.

Objective: The study aimed to synthesize 1,4-disubstituted-1,2,3-bistriazoles by optimized copper( I)-catalyzed alkyne-azide cycloaddition (CuAAC) and evaluate their antifungal and antitrypanosomastid activities.

Method: The synthesis of symmetrical bistriazoles with diazides as spacers was planned to be performed following the CuAAC reaction strategy. For evaluation of best conditions for the synthesis of symmetrical bistriazoles hex-1-yne 2 was chosen as leading compound, and a variety of catalysts were employed, choosing (3:1) alkyne:diazide stoichiometric relationship employing CuSO4.5H2O as the best condition. For the preparation of diversity in the synthesis of symmetrical bistriazoles, a 1,3-diazide-propan-2-ol 1a and 1,3-diazidepropane 1b were reacted with seven different alkynes, furnishing eleven symmetrical bistriazoles 9-13a,b and 14a. All compounds were essayed to cultures of promastigotes of L. amazonensis (1 x 106 cells mL-1) in the range of 0.10 - 40.00 µg mL-1 and incubated at 25ºC. After 72 h of incubation, the surviving parasites were counted. For antifungal assay, the minimum inhibitory concentrations (MIC) for yeasts and filamentous fungi were determined. Each compound was tested in 10 serial final concentrations (64 to 0.125 µg mL-1).

Results: Eleven 1,4-disubstituted-1,2,3-bistriazoles were synthesized and their structures were confirmed by IR, 1H and 13C-NMR and Mass spectral analysis. The antifungal and antitrypanosomastid activities were evaluated. The best result to antifungal activity was reached by bistriazole 11a that showed the same MIC of fluconazole (32 µg mL-1) against Candida krusei ATCC 6258, an emerging and potentially multidrug-resistant fungal pathogen. Due to their intrinsically biological activity versatility, five derivatives compounds showed leishmanicidal inhibitory activity between 15.0 and 20.0% at concentrations of 20 and 40.0 µg mL-1. Among these compounds the derivative 13a showed best IC50 value of 63.34 µg mL-1 (182.86 µM).

Conclusion: The preliminary and promising results suggest that bistriazole derivatives, especially compound 13a, could represent an innovative scaffold for further studies and development of new antifungal and anti-parasitic drug candidates.

Keywords: Antifungal activity, antitrypanosomastid activity, fungi, symmetrical bistriazoles, CuAAC methodology, Mass spectral analysis.

[1]
Huisgen, R. 1,3-Dipolar cycloadditions. Past and future. Angew. Chem. Int. Ed. Engl., 1963, 2(10), 565-598.
[2]
Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984, Vol. 1 Ch. 1, pp. 1-176.
[3]
Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click chemistry, diverse chemical function from a few good reactions. Angew. Chem. Int. Ed., 2001, 40(11), 2004-2021.
[4]
Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise huisgen cycloaddition process, copper(I)-catalyzed regioselective ligation of azides and terminal alkynes. Angew. Chem. Int. Ed., 2002, 41(14), 2596-2599.
[5]
Tornøe, C.W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase, [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem., 2002, 67(9), 3057-3064.
[6]
Zhang, L.; Chen, X.; Xue, P.; Sun, H.Y.; Williams, I.D.; Sharpless, K.B.; Fokin, V.V.; Jia, G. Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J. Am. Chem. Soc., 2005, 127(46), 15998-15999.
[7]
Rasmussen, L.K.; Boren, B.C.; Fokin, V.V. Ruthenium-catalyzed cycloaddition of aryl azides and alkynes. Org. Lett., 2007, 9(26), 5337-5339.
[8]
Eicher, T.; Hauptmann, S.; Speicher, A. The chemistry of heterocycles, structure, reactions, syntheses, and applications, 3rd ed; John Wiley & Sons: New Jersey, 2013.
[9]
Haider, S.; Alam, M.S.; Hamid, H. 1, 2, 3-Triazoles, scaffold with medicinal significance. Inflamm. Cell Signal., 2014, 1, e95.
[10]
Ferreira, V.F.; Rocha, D.R.; Silva, F.C.; Ferreira, P.G.; Boechat, N.A.; Magalhães, J.L. Novel 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole derivatives, a patent review (2008-2011). Expert Opin. Ther. Patents., 2013, 23(3), 319-331.
[11]
Therin, C.; Levesque, R.C. Molecular basis of antibiotic resistance and beta-lactamase inhibition by mechanism-based inactivators. Perspectives and future directions. FEMS Microbiol. Rev., 2000, 24(3), 251-262.
[12]
Khan, F.Y.; Elhiday, A.; Khudair, I.F.; Youssef, H.; Omran, A.H.; Alsamman, S.H.; Elhamid, M. Evaluation of the use of piperacillin/ tazobactam (Tazocin®) at Hamad General Hospital, Qatar. Are there unjustified prescriptions? Infect. Drug Resist., 2012, 5(1), 17-21.
[13]
Blackwell, C.C.; Freimer, E.H.; Tuke, G.C. In vitro evaluation of the new oral cephalosporin cefatrizine, comparison with other cephalosporins. Antimicrob. Agents Chemother., 1976, 10(2), 288-292.
[14]
Corrado, C.; Flugy, A.M.; Taverna, S.; Raimondo, S.; Guggino, G.; Karmali, R.; Leo, G.D.; Alessandro, R. Carboxyamidotriazole-orotate inhibits the growth of imatinib-resistant chronic myeloid leukaemia cells and modulates exosomes-stimulated angiogenesis. PLoS One, 2012, 7(8), e42310.
[15]
Agalave, S.G.; Maujan, S.R.; Pore, V.S. Click chemistry, 1,2,3-triazoles as pharmacophores. Chem. Asian J., 2011, 6(10), 2696-2718.
[16]
Das, K.; Bauman, J.D.; Rim, A.S.; Dharia, C.; Clark, Jr, A.D.; Camarasa, M.J.; Balzarini, J.; Arnold, E. Crystal structure of tertbutyldimethylsilylspiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket. J. Med. Chem., 2011, 54(8), 2727-2737.
[17]
Zheng, Z.J.; Wang, D.; Xu, Z.; Xu, L.W. Synthesis of bi- and bis-1,2,3-triazoles by copper-catalyzed Huisgen cycloaddition, a family of valuable products by click chemistry. Beilstein J. Org. Chem., 2015, 11, 2557-2576.
[18]
Li, Y.; Huffman, J.C.; Flood, A.H. Can terdentate 2,6-bis(1,2,3-triazol-4-yl) pyridines form stable coordination compounds? Chem. Commun., 2007, 2692-2694.
[19]
Scott, S.Ø.; Gavey, E.L.; Lind, S.J.; Gordon, K.C.; Crowley, J.D. Self-assembled palladium(II) “click” cages, synthesis, structural modification and stability. Dalton Trans., 2011, 40(45), 12117-12124.
[20]
Camp, C.; Dorbes, S.; Picard, C.; Benoist, E. Efficient and tunable synthesis of new polydentate bifunctional chelating agents using click chemistry. Tetrahedron Lett., 2008, 49(12), 1979-1983.
[21]
Ruan, Y.B.; Yu, Y.; Li, C.; Bogliotti, N.; Tang, J.; Xie, J. Triazolyl benzothiadiazole fluorescent chemosensors, a systematic investigation of 1,4- or 1,5-disubstituted mono- and bis-triazole derivatives. Tetrahedron, 2013, 69(23), 4603-4608.
[22]
Midya, G.C.; Paladhi, S.; Bhowmik, S.; Saha, S.; Dash, J. Design and synthesis of an on-off “click” fluorophore that executes a logic operation and detects heavy and transition metal ions in water and living cells. Org. Biomol. Chem., 2013, 11(18), 3057-3063.
[23]
Hemamalini, A.; Das, T.M. Design and synthesis of sugar-triazole low molecular weight gels as mercury ion sensor. New J. Chem., 2013, 37(8), 2419-2425.
[24]
Xu, H.R.; Li, K.; Liu, Q.; Wu, T.M.; Wang, M.Q.; Hou, J.T.; Huang, Z.; Xie, Y.M.; Yu, X.Q. Dianthracene-cyclen conjugate, the first equal-equivalent responding fluorescent chemosensor for Pb2+ in aqueous solution. Analyst, 2013, 138(8), 2329-2334.
[25]
Fischer, C.; Weber, E. Bis-calix [4] arene-based podants using the bridge position as a constructive mode of subunit connection. J. Inclusion. Phenom. Macrocyclic. Chem., 2014, 79(1-2), 151-160.
[26]
Bryant, J.J.; Lindner, B.D.; Bunz, U.H.F. Water-Soluble Bis-triazolyl Benzochalcogendiazole Cycloadducts as Tunable Metal Ion Sensors. J. Org. Chem., 2013, 78(3), 1038-1044.
[27]
Hung, H.C.; Cheng, C.W.; Ho, I.T.; Chung, W.S. Dual-mode recognition of transition metal ions by bis-triazoles chained pyrenes. Tetrahedron Lett., 2009, 50(3), 302-305.
[28]
Hung, H.C.; Cheng, C.W.; Wang, Y.Y.; Chen, Y.J.; Chung, W.S. Highly selective fluorescent sensors for Hg2+ and Ag+ based on bis-triazole-coupled polyoxyethylenes in MeOH solution. Eur. J. Org. Chem., 2009, 36, 6360-6366.
[29]
Huang, H.J.; Fang, H.Y.; Chir, J.L.; Wu, A. Effect of bis-triazoles on a ribose-based fluorescent sensor. Luminescence, 2011, 26(6), 518-522.
[30]
Romero, T.; Orenes, R.A.; Tárraga, A.; Molina, P. Preparation, Structural characterization, electrochemistry, and sensing properties toward anions and cations of ferrocene-triazole derivatives. Organometallics, 2013, 32(20), 5740-5753.
[31]
Zhou, M.; Zhang, X.; Bai, M.; Shen, D.; Xu, B.; Kao, J.; Ge, X.; Achilefu, S. Click reaction-mediated functionalization of near-infrared pyrrolopyrrole cyanine dyes for biological imaging applications. RSC Adv, 2013, 3(19), 6756-6758.
[32]
White, N.G.; Beer, P.D. A rotaxane host system containing integrated triazole C–H hydrogen bond donors for anion recognition. Org. Biomol. Chem., 2013, 11(8), 1326-1333.
[33]
Karuturi, R.; Al-Horani, R.A.; Mehta, S.C.; Gailani, D.; Desai, U.R. Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site. J. Med. Chem., 2013, 56(6), 2415-2428.
[34]
Mulla, K.; Shaik, H.; Thompson, D.W.; Zhao, Y. TTFV-based molecular tweezers and macrocycles as receptors for fullerenes. Org. Lett., 2013, 15(17), 4532-4535.
[35]
Isaacman, M.J.; Corigliano, E.M.; Theogarajan, L.S. Stealth Polymeric vesicles via metal-free click coupling. Biomacromolecules, 2013, 14(9), 2996-3000.
[36]
Krim, J.; Taourirte, M.; Engels, J.W. Synthesis of 1,4-disubstituted mono and bis-triazolocarbo-acyclonucleoside analogues of 9-(4-hydroxybutyl) guanine by Cu(I)-catalyzed click azide-alkyne cycloaddition. Molecules, 2012, 17(1), 179-190.
[37]
Jervis, P.J.; Moulis, M.; Jukes, J.P.; Ghadbane, H.; Cox, L.R.; Cerundolo, V.; Besra, G.S. Towards multivalent CD1d ligands, synthesis and biological activity of homodimeric α-galactosyl ceramide analogues. Carbohydr. Res., 2012, 356(9-10), 152-162.
[38]
Westermann, B.; Dörner, S.; Brauch, S.; Schaks, A.; Heinke, R.; Stark, S.; van Delft, F.L.; van Berkel, S.S. CuAAC-mediated diversification of aminoglycoside–arginine conjugate mimics by non-reducing di- and trisaccharides. Carbohydr. Res., 2013, 371, 61-67.
[39]
Singh, M.K.; Tilak, R.; Nath, G.; Awasthi, S.K.; Agarwal, A. Design, synthesis and antimicrobial activity of novel benzothiazole analogs. Eur. J. Med. Chem., 2013, 63, 635-644.
[40]
Kumar, K.; Carrère-Kremer, S.; Kremer, L.; Guérardel, Y.; Biot, C.; Kumar, V. Azide–alkyne cycloaddition en route towards 1H-1,2,3-triazole-tethered β-lactam–ferrocene and β-lactam–ferrocenyl chalcone conjugates, synthesis and in vitro anti-tubercular evaluation. Dalton Trans., 2013, 42(5), 1492-1500.
[41]
Anthony, P.; Bashir, N.; Parveen, R. Regioselective synthesis of 1,4-disubstituted 1,2,3-bistriazoles and their anti-fungal and anti-oxidant evaluation. Asian J. Biomed. Pharm. Sci, 2014, 4(33), 9-13.
[42]
Jurášek, M.; Džubák, P.; Sedlák, D.; Dvořáková, H.; Hajdúch, M.; Bartůněk, P.; Drašar, P. Preparation, preliminary screening of new types of steroid conjugates and their activities on steroid receptors. Steroids, 2013, 78(3), 356-361.
[43]
Kamal, A.; Shankaraiah, N.; Reddy, C.R.; Prabhakar, S.; Markandeya, N.; Srivastava, H.K.; Sastry, G.N. Synthesis of bis-1,2,3-triazolo-bridged unsymmetrical pyrrolobenzodiazepine trimers via ‘click’ chemistry and their DNA-binding studies. Tetrahedron, 2010, 66(29), 5498-5506.
[44]
Dügdü, E.; Ünlüer, D.; Çelik, F.; Sancak, K.; Karaoglu, S.A.; Özel, A. Synthesis of novel symmetrical 1,4-disubstituted 1,2,3-bistriazole derivatives via ‘Click Chemistry’ and their biological evaluation. Molecules, 2016, 21(7), 659-671.
[45]
Priyanka, K.G.; Mishra, A.K.; Kantheti, S.; Narayan, R.; Raju, K.V.S.N. Synthesis of triazole ring-containing pentol chain extender and its effect on the properties of hyperbranched polyurethane-urea coatings. J. Appl. Polym. Sci., 2012, 126(6), 2024-2034.
[46]
Konda, S.; Rao, P.; Oruganti, S. Click chemistry route to tricyclic monosaccharide triazole hybrids, design and synthesis of substituted hexahydro-4H-pyrano[2,3-f] [1,2,3]triazolo[5,1-c][1,4]oxa-zepines. RSC Adv, 2014, 4(109), 63962-63965.
[47]
Li, W.; Xia, Y.; Fan, Z.; Qu, F.; Wu, Q.; Peng, L. Bitriazolyl acyclonucleosides with antiviral activity against Tobacco Mosaic virus. Tetrahedron Lett., 2008, 49(17), 2804-2809.
[48]
Camp, C.; Dorbes, S.; Picard, C.; Benoist, E. Efficient and tunable synthesis of new polydentate bifunctional chelating agents using click chemistry. Tetrahedron Lett., 2008, 49(12), 1979-1983.
[49]
Kwon, M.; Jang, Y.; Yoon, S.; Yang, D.; Jeon, H.B. Unusual Cu(I)-catalyzed 1,3-dipolar cycloaddition of acetylenic amides, formation of bistriazoles. Tetrahedron Lett., 2012, 53(13), 1606-1609.
[50]
Macedo-Silva, S.T.; Urbina, J.A.; Souza, W.; Rodrigues, J.C.F. In Vitro activity of the antifungal azoles itraconazole and posaconazole against Leishmania amazonenses. PLoS One, 2013, 8(12), e83247.
[51]
Lazardi, K.; Urbina, J.A.; Souza, W. Ultrastructural alterations induced by ICI 195,739, a bistriazole derivative with strong antiproliferative action against Trypanosoma (Schizotrypanum) cruzi. Antimicrob. Agents Chemother., 1991, 35(4), 736-740.
[52]
Bakunov, S.A.; Bakunova, S.M.; Wenzler, T.; Ghebru, M.; Werbovetz, K.A.; Brun, R.; Tidwell, R.R. Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3-triazoles. J. Med. Chem., 2010, 53(1), 254-272.
[53]
Ferreira, S.B.; Costa, M.S.; Boechat, N.; Bezerra, R.J.; Genestra, M.S.; Canto-Cavalheiro, M.M.; Kover, W.B.; Ferreira, V.F. Synthesis and evaluation of new difluoromethyl azoles as antileishmanial agents. Eur. J. Med. Chem., 2007, 42(11-12), 1388-1395.
[54]
Low, C-H.; Rotstein, C. Emerging fungal infections in immunocompromised patients. F1000 Med. Rep., 2011, 3, 14.
[55]
Denning, D.W.; Hope, W.W. Therapy for fungal diseases, opportunities and priorities. Trends Microbiol., 2010, 18(5), 195-204.
[56]
Roemer, T.; Krysan, D.J. Antifungal drug development, challenges, unmet clinical needs, and new approaches. Cold Spring Harb. Perspect. Med., 2014, 4(5), a019703.
[57]
Whaley, S.G.; Berkow, E.L.; Rybak, J.M.; Nishimoto, A.T.; Barker, K.S.; Rogers, P. Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species. Front. Microbiol., 2016, 7, 2173.
[58]
Pfaller, M.A.; Diekema, D.J.; Gibbs, D.L.; Newell, V.A.; Nagy, E.; Dobiasova, S.; Rinaldi, M.; Barton, R.; Veselov, A. Candida krusei, a multidrug-resistant opportunistic fungal pathogen, geographic and temporal trends from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J. Clin. Microbiol., 2008, 46(2), 515-521.
[59]
Lass-Flörl, C.; Mayr, A.; Perkhofer, S.; Hinterberger, G.; Hausdorfer, J.; Speth, C.; Fille, M. Activities of antifungal agents against yeasts and filamentous fungi, assessment according to the methodology of the European Committee on Antimicrobial Susceptibility Testing. Antimicrob. Agents Chemother., 2008, 52(10), 3637-3641.
[60]
Patil, A.; Salunkhe, R. Hydrotrope promoted in-situ azidonation followed by copper catalyzed regioselective synthesis of β-hydroxytriazoles. Res. Chem. Intermed., 2017, 43(7), 4175-4187.
[61]
Nguyen, T.V.Q.; Yoo, W-J.; Kobayashi, S. Effective formylation of amines with carbon dioxide and diphenylsilane catalyzed by chelating bis(tzNHC) rhodium complexes. Angew. Chem. Int. Ed., 2015, 54(32), 9209-9212.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 15
ISSUE: 4
Year: 2019
Page: [400 - 408]
Pages: 9
DOI: 10.2174/1573406414666181024111522
Price: $58

Article Metrics

PDF: 31
HTML: 4
EPUB: 1
PRC: 1