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Synthesis and in vitro biological evaluation of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives as antifungal compounds fluconazole analogues

  • Armando Zambrano-Huerta
  • Damián David Cifuentes-Castañeda
  • Joanatan Bautista-Renedo
  • Hugo Mendieta-Zerón
  • Roberto Carlos Melgar-Fernández
  • Sergio Pavón-Romero
  • Macario Morales-Rodríguez
  • Bernardo A. Frontana-Uribe
  • Nelly González-Rivas
  • Erick Cuevas-YañezEmail author
Original Research
  • 29 Downloads

Abstract

A novel series of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives was synthesized from 1-aryl-1,3-diazidopropan-2-ol derivatives and diverse alkynes using copper catalyzed azide-alkyne cycloaddition in the key step. Most of synthesized compounds showed high activity against Candida spp. strains at a 0.04–0.5 μg/mL concentration range compared to Itraconazole and Fluconazole (MIC 2.56 and 1.28 μg/mL, respectively), which were used as reference compounds. A 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivative (R1 = F and R2 = cyclopropyl) displayed an outstanding selectivity against Candida albicans and Candida krusei (MIC = 0.0075 µg/mL). Moreover, Artemia salina bioassay on 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives revealed low toxicity in this kind of compounds. In addition, molecular docking studies suggest good binding affinity of halogen atoms in some 1-aryl-1,3-diazidopropan-2-ol derivatives to HEME group present in 14-alpha demethylase (CYP51), which might explain the high antifungal activity found in these compounds.

Keywords

1,2,3-Triazoles Antifungal Click chemistry Fluconazole analogues 

Notes

Acknowledgements

This work was supported by COMECYT (fellowship for AZH) and ASCILA (fellowship for DDCC). Financial support from CONACYT is also gratefully acknowledged. The authors would like to thank Signa S.A. de C. V. for some kindly donated solvents and reagents and to N. Zavala, A. Nuñez, and L. Triana for the technical support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2317_MOESM1_ESM.pdf (7.1 mb)
Supplementary Data

References

  1. Agalave SG, Maujan SR, Pore VS (2011) Click chemistry: 1,2,3-Triazoles as pharmacophores. Chem Asian J 6:2696–2718CrossRefGoogle Scholar
  2. Aher NG, Pore VS, Mishra NN, Kumar A, Shukla PK, Sharma A, Bhat MK (2009) Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole analogues. Bioorg Med Chem Lett 19:759–763CrossRefGoogle Scholar
  3. Andes D, van Ogtrop M (1999) Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother 43:2116–2120CrossRefGoogle Scholar
  4. Aufort M, Herscovici J, Bouhours P, Moreau N, Girard C (2008) Synthesis and antibiotic activity of a small molecules library of 1,2,3-triazole derivatives. Bioorg Med Chem Lett 18:1195–1198CrossRefGoogle Scholar
  5. Bock VD, Hiemstra H, van Maarseveen JH (2006) CuI-catalyzed alkyne–azide “Click” cycloadditions from a mechanistic and synthetic perspective. Eur J Org Chem 51–68Google Scholar
  6. Bonandi E, Christodoulou MS, Fumagalli G, Perdicchia D, Rastelli G, Passarella D (2017) The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov Today 22:1572–1581CrossRefGoogle Scholar
  7. Carballo JL, Hernández-Inda ZL, Pérez P, García-Grávalos MD (2002) A comparison between two brine shrimp assays to detect in vitro cytotoxicity in marine natural products. BMC Biotechnol 2:17, http://www.biomedcentral.com/1472-6750/2/17 CrossRefGoogle Scholar
  8. Dickinson RP, Bell AS, Hitchcock CA, Narayanaswami S, Ray SJ, Richardson K, Troke PF (1996) Novel antifungal 2-aryl-i-(ih-1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against Aspergillus fumigatus. Bioorg Med Chem Lett 6:2031–2036CrossRefGoogle Scholar
  9. Dismukes WE (1988) Azole antifungal drugs: old and new. Ann Intern Med 109:177–179CrossRefGoogle Scholar
  10. Dutcher R (2008) Candidemia: optimizing the dose of fluconazole. US Pharm 33:HS14–HS19Google Scholar
  11. Eto H, Kaneko Y, Sakamotoa T (2000) New antifungal 1,2,4-triazoles with Difluoro(heteroaryl)methyl moiety. Chem Pharm Bull 48:982–990CrossRefGoogle Scholar
  12. Haider S, Alam MS, Hamid H (2014) 1,2,3-Triazoles: scaffold with medicinal significance. Inflamm Cell Signal 1:e95Google Scholar
  13. Heeres J, Meerpoel L, Lewi P (2010) Conazoles. Molecules 15:4129–4188CrossRefGoogle Scholar
  14. Heravia MM, Motamedi R (2004) Synthesis of some new propanol derivatives analogous to fluconazole. Phosphorus Sulfur 179:2329–2334CrossRefGoogle Scholar
  15. Irfan M, Aneja B, Yadava U, Khan SI, Manzoor N, Daniliuc CG, Abid M (2015) Synthesis, QSAR and anticandidal evaluation of 1,2,3-triazoles derived from naturally bioactive scaffolds. Eur J Med Chem 93:246–254CrossRefGoogle Scholar
  16. Lass-Flörl C (2011) Triazole antifungal agents in invasive fungal infections: a comparative review. Drugs 71:2405–2419CrossRefGoogle Scholar
  17. Layton-Tovar CF, Cuevas-Yañez E, Velasco-Montejo BE, Mendieta-Zerón H (2014) High susceptibility of Candida albicans ATCC 10231 to tetrahydrofuranosyl-1,2,3-triazoles obtained by click chemistry. Rev Boliv Quím 31:15–21Google Scholar
  18. Lebouvier N, Pagniez F, Duflos M, Le Pape P, Na YM, Le Baut G, Borgne M (2007) Synthesis and antifungal activities of new fluconazole analogues with azaheterocycle moiety. Bioorg Med Chem Lett 17:3686–3689CrossRefGoogle Scholar
  19. Meldal M, Tornoe CW (2008) Cu-catalyzed azide-alkyne cycloaddition. Chem Rev 108:2952–3015CrossRefGoogle Scholar
  20. Miyazaki M, Horii T, Hata K, Watanabe NA, Nakamoto K, Tanaka K, Shirotori S, Murai M, Inoue S, Matsukura M, Abe S, Yoshimatsu K, Asada M (2011) In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrob Agents Chemother 55:4652–4658CrossRefGoogle Scholar
  21. Moses ME, Moorhouse AD (2007) The growing applications of click chemistry. Chem Soc Rev 36:1249–1262CrossRefGoogle Scholar
  22. Pore VS, Aher NG, Kumar M, Shukla PK (2006) Design and synthesis of fluconazole/bile acid conjugate using click reaction. Tetrahedron 62:11178–11186CrossRefGoogle Scholar
  23. Pore VS, Jagtap MA, Agalave SG, Pandey AK, Siddiqi MI, Kumar V, Shukla PK (2012) Synthesis and antifungal activity of 1,5-disubstituted-1,2,3-triazole containing fluconazole analogues. Med Chem Commun 3:484–488CrossRefGoogle Scholar
  24. Reed RJ, Muench H (1938) A simple method of estimating fifty per cent endpoints. Am J Hyg 27:493–497Google Scholar
  25. Rex JH, Alexander BD, D. Arthington-Skaggs AB, Brown SD, Chaturvedi V, Ghannoum MA, Espinel-Ingroff A, Knapp CC, Ostrosky-Zeichner L, Pfaller MA, Sheehan DJ, Walsh TJ (2008) National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of yeasts; Approved Standard-Third Edition. M27-A3vol. 28 Clinical and Laboratory Standards Institute, WayneGoogle Scholar
  26. Richardson K, Brammer KW, Marriott MS, Troke PF (1985) Activity of UK-49,858, a Bis-Triazole Derivative, Against Experimental Infections with Candida albicans and Trichophyton mentagrophytes. Antimicrob Agents Chemother 27:832–835CrossRefGoogle Scholar
  27. Rogers TE, Galgiani JN (1986) Activity of Fluconazole (UK 49,858) and Ketoconazole against Candida albicans in vitro and in vivo. Antimicrob Agents Chemother 30:418–422CrossRefGoogle Scholar
  28. Saag MS, Dismukes WE (1988) Azole antifungal agents: emphasis on new Triazoles. Antimicrob Agents Chemother 31:1–8CrossRefGoogle Scholar
  29. Sagatova AA, Keniya MV, Wilson RJ, Monk BC, Tyndall JDA (2015) Structural insights into binding of the antifungal drug fluconazole to Saccharomyces cerevisiae lanosterol 14α-demethylase. Antimicrob Agents Chemother 59:4982–4989CrossRefGoogle Scholar
  30. Salake AB, Chothe AS, Nilewar SS, Khilare M, Rutuja S, Meshram RS, Pandey AA, Kathiravan MK (2014) Design, synthesis, and evaluations of antifungal activity of novel phenyl(2H-tetrazol-5-yl)methanamine derivatives. J Chem Biol 7:29–35CrossRefGoogle Scholar
  31. Sam TW (1993) Toxicity testing using the brine shrimp: Artemia salina. In: Colegate SM (ed.) Bioactive Natural Product, Detection, Isolation, and Structural Determination. CRC Press, New York, p 441–456Google Scholar
  32. Silvestri R, Artico M, La Regina G, Di Pasquali A, De Martino G, D’Auria FD, Nencioni L, Palamara AT (2004) Imidazole Analogues of Fluoxetine, a Novel Class of Anti-Candida Agents. J Med Chem 47:3924–3926CrossRefGoogle Scholar
  33. Subhas S, Veliyath SK, Mahendra Kumar CB (2012) Review on substituted 1,2,4-triazoles as potent antifungal and antibacterial agents. Int J Res Pharm Sci 3:326Google Scholar
  34. Thirumurugan P, Matosiuk D, Jozwiak K (2013) Click chemistry for drug development and diverse chemical−biology applications. Chem Rev 113:4905–4979CrossRefGoogle Scholar
  35. Turker AU, Camper ND (2002) Biological activity of common mullein, a medicinal plant. J Ethnopharmacol 82:117–125CrossRefGoogle Scholar
  36. Wang S, Zhang L, Jin Y, Tang JH, Su H, Yu S, Ren H (2014) Synthesis and evaluation of some substituted heterocyclic fluconazole analogues as antifungal agents. Asian J Chem 26:2362–2364CrossRefGoogle Scholar
  37. Wang Y, Xu K, Bai G, Huang L, Wu Q, Pan W, Yu S (2014) Synthesis and antifungal activity of novel triazole compounds containing piperazine moiety. Molecules 19:11333–11340CrossRefGoogle Scholar
  38. Warnock DW, Burke J, Cope NJ, Johnson EM, von Fraunhofer NA, Williams EW (1988) Fluconazole resistance in candida glabrata. Lancet 332:1310CrossRefGoogle Scholar
  39. Woradulayapinij W, Soonthornchareonnon S, Wiwat C (2005) In vitro HIV type 1 reverse transcriptase inhibitory activities of Thai medicinal plants and Canna indica L. rhizomes. J Ethnopharmacol 101:84–89CrossRefGoogle Scholar
  40. Xu L, Muller MR, Yu X, Zhu BQ (2009) Improved chiral synthesis of ravuconazole. Synth Commun 39:1611–1625CrossRefGoogle Scholar
  41. Zhang YY, Mi JL, Zhou CH, Zhou XD (2011) Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities. Eur J Med Chem 46:4391–4402CrossRefGoogle Scholar
  42. Zou Y, Zhao Q, Liao J, Hua H, Yu S, Chai X, a, Xu M, Wu Q (2012) New triazole derivatives as antifungal agents: Synthesis via click reaction, in vitro evaluation and molecular docking studies. Bioorg Med Chem Lett 22:2959–2962CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Armando Zambrano-Huerta
    • 1
    • 3
  • Damián David Cifuentes-Castañeda
    • 1
  • Joanatan Bautista-Renedo
    • 1
  • Hugo Mendieta-Zerón
    • 2
  • Roberto Carlos Melgar-Fernández
    • 3
  • Sergio Pavón-Romero
    • 4
  • Macario Morales-Rodríguez
    • 4
  • Bernardo A. Frontana-Uribe
    • 1
  • Nelly González-Rivas
    • 1
  • Erick Cuevas-Yañez
    • 1
    Email author
  1. 1.Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM. Universidad Autónoma del Estado de MéxicoTolucaMexico
  2. 2.Facultad de MedicinaUniversidad Autónoma del Estado de MexicoTolucaMexico
  3. 3.Signa S.A. de C.V., Av. Industria Automotriz No. 301, Zona Industrial TolucaTolucaMexico
  4. 4.Departamento de Microbiología, Facultad de QuímicaUniversidad Autónoma del Estado de MexicoTolucaMexico

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