1,2,4-Triazole Derivatives for Synthesis of Biologically Active Compounds

Introduction

1,2,4-Triazole (abbreviated Htrz when used as a ligand in coordination compounds) is one of the two isomers of triazole (C2H3N3), a five-membered ring consisting of two carbon atoms and three nitrogen atoms.1,2,4-Triazole and its derivatives have a wide range of applications. [1]

1,2,4-Triazole is a coplanar molecule with both C-N and N-N bond lengths in the range of 136-132 pm, consistent with aromatic compounds.[2] Although two reciprocal isomers of 1,2,4-triazole can be envisioned, in fact only one form exists.

1,2,4-Triazolium is amphoteric and both protonation and deprotonation of nitrogen occur readily in aqueous solution. 1,2,4-Triazolium ions (C2N3H4+) have a pKa of 2.45. The neutral molecules have a pKa of 10.26.[3]

Synthesis and Occurrence

1,2,4-Triazoles can be prepared by the Einhorn-Brunner Reaction or the Pellizzari Reaction. Unsubstituted 1,2,4-triazoles can be prepared from thiosemicarbazide by formic acid acylation followed by cyclization of 1-formyl-3-aminothiourea to 1,2,4-trimethylazole-3(5)-thiols; oxidation of the thiols by nitric acid or hydrogen peroxide yields 1,2,4-triazoles. [5]

Fig2. Portion of the structure of {[Fe(triazolate)(triazole)2](BF4)}n.[4]

1,2,4-Triazole possesses unique and excellent chemical properties such as dipole interaction, solubility, rigidity, and hydrogen bonding ability. Not only that, 1,2,4-Triazole also acts as a bioelectronic isoform of carboxylic, amide, and acidic groups, and therefore exists in many drug structures, and has become one of the preferred backbones for the design and development of new drugs.[6][7] They are widely used in a variety of clinical drugs, including the antifungal drugs fluconazole and itraconazole[8] as well as the plant growth regulator paclobutrazol.[9] And in coordination chemistry, the 1,2,4-triazole anion is often used as a bridging ligand.[10]

Application

1,2,4-Triazole derivatives have been actively used in the preparation of many bioactive substances and functional materials.[11] Currently, there are about 15 marketed drugs and 50 drug candidates containing 1,2,4-triazole structures.[12]

Figure 3. Examples of medical and technical applications of 1,2,4-triazole

Of the drug molecules shown above, Compound 1 Fluconazole and Compound 2 Ribavirin have been successfully commercialized as antifungal and antiviral drugs, respectively. Compound 3 anti-HIV-1 drug Doravirine was approved for marketing by the FDA in 2018. Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that also contains a 1,2,4-triazole structure in its structure.

Technological applications of 1,2,4-triazole include corrosion inhibitors (e.g., compound 4 in Fig. 3) [13], ionic liquids (e.g., compound 5 in Fig. 3) [14], metal complexing agents [15], organic polymers for light-emitting devices [16], and dendritic polymers [17]. Among them, the inhibition efficiency of corrosion inhibitors increases with the electron density around their molecules, thus BBATT has been shown to be a better corrosion inhibitor than EBATT. Furthermore, ionic liquids based on aryl/alkyl substituted imidazolium salts constitute a new generation of ionic liquids with high flexibility. More notably, the deprotonated parent 1,2,4-triazole has recently been shown to be an active acyl transfer catalyst suitable for ester amination and ester exchange. [18]

Reference

1. Potts K. T. (1961). "The Chemistry of 1,2,4-Triazoles". Chemical Reviews. 61 (2): 87–127.  https://doi.org/10.1021/cr60210a001

2. Jeffrey, G. A.; Ruble, J. R.; Yates, J. H. (1983). "Neutron diffraction at 15 and 120 K and ab initio molecular-orbital studies of the molecular structure of 1,2,4-triazole". Acta Crystallographica Section B: Structural Science. 39 (3): 388–394.  https://doi.org/10.1107/S010876818300258X

3. Garratt, Peter J. (1996). "1,2,4-Triazoles". Comprehensive Heterocyclic Chemistry II. pp. 127–163.  https://doi.org/10.1016/B978-008096518-5.00080-0

4. Grosjean, Arnaud; Négrier, Philippe; Bordet, Pierre; Etrillard, Céline; Mondieig, Denise; Pechev, Stanislav; Lebraud, Eric; Létard, Jean-François; Guionneau, Philippe (2013). "Crystal Structures and Spin Crossover in the Polymeric Material [Fe(HTRZ)2(TRZ)](BF4) Including Coherent-Domain Size Reduction Effects" (PDF). European Journal of Inorganic Chemistry. 2013 (5–6): 796–802.  https://doi.org/10.1002/ejic.201201121

5. C. Ainsworth (1960). "1,2,4-Triazole". Organic Syntheses. 40: 99.  https://doi.org/10.15227/orgsyn.040.0099

6. Keri, Rangappa S.; Patil, Siddappa A.; Budagumpi, Srinivasa; Nagaraja, Bhari Mallanna (2015). "Triazole: A Promising Antitubercular Agent". Chemical Biology & Drug Design. 86 (4): 410–423.  https://doi.org/10.1111/cbdd.12527

7. Kaur, Ramandeep; Ranjan Dwivedi, Ashish; Kumar, Bhupinder; Kumar, Vinod (2016). "Recent Developments on 1,2,4-Triazole Nucleus in Anticancer Compounds: A Review". Anti-Cancer Agents in Medicinal Chemistry. 16 (4): 465–489.  https://doi.org/10.2174/1871520615666150819121106

8. Kathiravan, Muthu K.; Salake, Amol B.; Chothe, Aparna S.; Dudhe, Prashik B.; Watode, Rahul P.; Mukta, Maheshwar S.; Gadhwe, Sandeep (2012). "The biology and chemistry of antifungal agents: A review". Bioorganic & Medicinal Chemistry. 20 (19): 5678–5698.  https://doi.org/10.1016/j.bmc.2012.04.045

9. Tesfahun, Wakjira (January 1, 2018). Yildiz, Fatih (ed.). "A review on: Response of crops to paclobutrazol application". Cogent Food & Agriculture. 4 (1): 1–9.  https://doi.org/10.1080/23311932.2018.1525169

10. Haasnoot, Jaap G. (2000). "Mononuclear, oligonuclear and polynuclear metal coordination compounds with 1,2,4-triazole derivatives as ligands". Coordination Chemistry Reviews. 200–202: 131–185.  https://doi.org/10.1016/S0010-8545(00)00266-6

11. For a general review, see Curtis A.D.M.; Jennings, N. in Comprehensive Heterocyclic Chemistry, 3rd edition, eds. A.R. Katritzky, C.A. Ramsden, E.F.V. Scriven, and R. J.K. Taylor Pergamon, Oxford, 2008. Vol. 5, p. 160.

12. www.drugbank.ca; accessed on August 2019.

13. John, S.; Joseph, A. Ind. Eng. Chem. Res. 2012, 51, 16633.

14. Meyer, D.; Strassner, T. J. Org. Chem. 2011, 76, 305.

15. Wang, Y.-L.; Zhang, N.; Liu, Q.-Y.; Shan, Z.-M.; Cao, R.; Wang, M.-S.; Luo, J.-J.; Yang, E.-L. Cryst. Growth&Design 2011, 11, 130.

16. Z. Liu, Y. X. Cheng, G. P. Su, L. X. Wang, X. B. Jing, and F. S. Wang, Synth. Met. 2003, 137, 1113.

17. Maes, W.; Verstappen, B.; Dehaen, W. Tetrahedron 2006, 62, 2677.

18. Yang, X.; Birman, V.B. Org. Lett. 2009, 11, 1499.