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
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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.
Keywords1,2,3-Triazoles Antifungal Click chemistry Fluconazole analogues
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.
- 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
- Dutcher R (2008) Candidemia: optimizing the dose of fluconazole. US Pharm 33:HS14–HS19Google Scholar
- Haider S, Alam MS, Hamid H (2014) 1,2,3-Triazoles: scaffold with medicinal significance. Inflamm Cell Signal 1:e95Google Scholar
- 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
- 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
- Reed RJ, Muench H (1938) A simple method of estimating fifty per cent endpoints. Am J Hyg 27:493–497Google Scholar
- 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
- 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
- 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