Design and Synthesis of Antifungal Compounds from 1,2,3-Triazoles through the Click Chemistry Approach
Ana Karla Estrada Valdés and Erick Cuevas-Yañez*
Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Mexico
Submission: February 12, 2019; Published: March 12, 2019
*Corresponding author: Erick Cuevas Yañez Carretera Toluca-Atlacomulco Km 14.5, Toluca, Estado de México, 50200, Autonomous University of the State of Mexico, Mexico
Tel:+919286990247 ; Email: firstname.lastname@example.org
How to cite this article: Ana K E V, Erick C-Y. Design and Synthesis of Antifungal Compounds from 1,2,3-Triazoles through the Click Chemistry Approach.
Organic & Medicinal Chem IJ. 2019; 8(2): 555734. DOI: 10.19080/OMCIJ.2019.08.555734
1,2,3-triazoles are easily prepared from CuAAC reaction and represent a potential source of antifungal compounds analogous to azole drugs. Accordingly, research groups have synthesized diverse 1,2,3-triazoles with modulated antifungal activity through the substituents in azide or alkyne precursors. A brief review of the state of the art about this topic is presented, focusing the increasing importance of developing new and more selective antifungal compounds
Fungal infections directly affect million people each year. Besides the invasive fungal infections on humans, the plants and animals considered as a primary source of food are also susceptible to diseases caused by these eukaryotic microbes. This necessity for antifungals not only for medical purposes, but also for uses in agriculture and livestock farming, causes a high demand for this kind of compounds. A relevant commercially known group of antifungal agents are the azole drugs group, which is characterized by containing imidiazole or 1,2,4-triazole, an azole, in their structures. Discovered in the 1960s, some representative examples of azole antifungal drugs are miconazole or clotrimazole which been used as antifungal agents since the end of the 1970s [1,2]. Other examples are propiconazole, introduced in the market in 1979, fluconazole and ketoconazole (1990), itraconazole (1992), and second-generation azole drugs as voriconazole (2002) and posconazole (2006) .
A part of the success of azoles as antifungal drugs resides on the heterocyclic moiety which is related to the ability to inhibit 14s-demethylase at fungi cell membrane and subsequent ergosterol synthesis blocking by interaction with the cytochrome p450 enzyme complex. Hence, the presence of azole ring is fundamental to achieve a significant biological activity .
On the other hand, CuAAC reaction has been recognized as one of the most important reactions for molecular assemblywhich is concomitant with one of simplest and visionary chemical concepts developed in this century [5-7]. In this reaction, the formation of a 1,2,3-triazole inherent in this process has been used as linkage unit in the building of complex molecular structures, and more recently, in the drug design for diverse purposes. In this regard, excellent reviews give a general idea about this topic [8-12]. Due to the high degree of similarity between 1,2,3-triazole, imidazole and 1,2,4-triazole, an initial hypothesis is that 1,2,3-triazoles would display antifungal activity similar to commercially available azole drugs. The structures of these heterocyclic systems are represented in (Figure 1).
as well as 1-benzyl-1,2,3-triazoles [2,14] and [3,15] resulted
active against strains of Candida albicans. Other 1,2,3-triazoles
(compounds 4 and 5, figure 2 bearing hydroxyl groups also
showed antifungal activity compared to fluconazole reference
standard [16,17]. Moreover, 1,2,3-triazole analogues to molecule
6 were available from CuAAC reaction of triclosan derivatives
and displayed a significant activity against Candida albicans
ATCC 10231 expressed in a high MIC50 and MIC90 [18,19].
Taking the advantages provided by CuAAC reaction and the
Click Chemistry concept, some research groups have designed
2-ol derivatives as promising fluconazole analogues. Thus,
was reacted with diverse benzyl, alkyl azides and also azido bile
acid derivatives to afford the corresponding triazoles 8 figure
3 [20-22]. An alternative strategy to increase the number of
molecules in a chemical library from CuAAC reaction consists in
changing the azide-alkyne group position on the reactive sites.
With this idea, diverse alkynes were treated with 1-Azido-2-(2,4-
difluoro-phenyl)-3-[1,2,4]triazol-1-yl-propan-2-ol (9) yielding
fluconazole analogues of type 10 [22-24]. All the compounds
were highly active against different strains of fungi which prove
that this kind of molecules possess an activity similar or higher
than fluconazole having as further benefit that synthesis of these
compounds is carried out with fewer reactions compared to the
commercially available compound.
Figure 3 Synthetic routes to prepare 2-aryl-1-(1,2,4-
These examples demonstrate that 1,2,3-triazoles are useful
structures for the design of antifungal compounds which offer
a great chance to drive the research in this area taking in to
consideration that the Click Chemistry will help to increase and
modulate the biological properties through simplest reactions
opening new trends in this area.
Layton TCF, 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. Bolivian J Chem 31: 15-21.
Velasco BE, López-Téllez G, González-Rivas N, García-Orozco I, Cuevas-Yañez E (2013) Catalytic activity of dithioic acid copper complexes in the alkyne-azide cycloaddition. Can J Chem 91: 292-299.