Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications

1The name triazole was first coined by Bladin in 1885 to assign the five-membered three nitrogen–containing heterocyclic aromatic ring system having molecular formula C2H3N3. After the discovery of triazole, its chemistry was developed gradually and speeded up with the establishment of several facile and convenient synthetic techniques along with its versatile interaction with biological systems. For example, discovery of antifungal activities of azole derivatives in 1944 led to the invention of fluconazole, itraconazole, voriconazole, posaconazole, efinaconazole, etc. (Figure 1; ). Of these, voriconazole and posaconazole are active against fluconazole-resistant strains of Candida. The mechanism of such antifungal action is also well-established which involves the inhibition of ergosterol synthesis and blocking of the P450-dependent enzyme (CYP 51). Triazole-type ring structure(s) can coordinate with the heme iron of the CYP enzyme.

2In addition, triazole heterocyclic structures are found to form many weak nonbond interactions with the receptors and enzymes in biological systems. These inherent properties of triazole compounds have established them as key chromophores with immense medicinal value and attract scientists of all disciplines, including chemical, agricultural, supramolecular, pharmaceutical, polymer, and materials sciences. Among the medicinal drugs, triazole-based antibacterial, antifungal, antiviral, anti-inflammatory, anticoagulant, antitubercular, antidiabetic, antioxidant, and anticancer drugs are available.

3The appearance of multidrug-resistant (MDR) pathogens, especially, resistance to triazole drugs makes microbial treatment less effective, a worse prognosis of infection, and problematic. For example, Candida albicans and Candida krusei strains (responsible for 75–88% of fungal infections) are resistant to the most common azole drug fluconazole. Azole-derived several drugs have also become resistant against A. fumigatus and C. glabrata strains. In addition, many adverse effects such as rash, diarrhea, headache, hepatotoxicity, and gastrointestinal problems including several severe problems (heart failure, renal failure, liver problems, Stevens–Johnson syndrome, etc.) are reported for many triazole drugs. Thus, the prudential development of new triazole drugs with bioisosteric replacement and molecular hybridization is necessary to overcome MDR pathogens and reduce the side effects of the available drugs. In this review, structural features, synthetic approaches, and biological properties of 1,2,3- and 1,2,4-triazoles are discussed, highlighting the related research works since 2015.

4Due to a wide range of applications across scientific disciplines, triazoles gained an exceptional structural motif and are notably related to the chemistry of triazoles. The basic skeleton of triazoles comprises a five-membered heterocyclic ring consisting of two carbon and three nitrogen atoms with the molecular formula C2H3N3. In the five-membered ring, a maximum of two types of positional arrangement of nitrogen atoms led to the formation of two substantial isomers, namely, 1,2,3-triazole (ν-triazole) and 1,2,4-triazole (s-triazole). Each of them shows mainly two tautomers depending on the hydrogen bonded to ring nitrogen (Figure 2). The 4H-1,2,3-triazole structure is nonaromatic and hence is discarded. All the atoms in both the triazoles are in sp 2 hybridized and are planar. Six pi (π) electrons are available in both forms, which are delocalized around the ring to generate their aromatic character. Moreover, the presence of 3 N atoms makes triazoles energy-rich heterocycles.

5When a benzene ring is fused at the 4,5-positions of 1,2,3-triazoles, it is termed benzotriazoles (Figure 2). In the monocyclic 1,2,3-triazoles, both 1H- and 2H-1,2,3-triazoles are generally in equilibrium in both solution and gas phases and exist as an equimolar mixture in the solid state. However, in an aqueous solution, 2H-1,2,3-triazole exists as major compared to the other tautomer (2H:1H = 2:1). The parent 1H-1,2,3-triazole is a clear liquid with a bp of 203°C, computed topological polar surface area of 41.6 Å2, and is soluble in H2O. Most of the 1,2,3-triazoles are prepared from azides. The presence of one pyrrole-type and two pyridine-type nitrogen atoms makes 1,2,3-triazole rings very stable and difficult for quaternization. It easily undergoes electrophilic substitution at carbon or at nitrogen.

6In 1,2,4-triazoles, the parent 1H-1,2,4-triazole is a white powder solid (mp 120–121°C, bp 260°C). Like 1H-1,2,3-triazole, it is very soluble in water. It is also soluble in organic solvents. The two tautomers (1H- and 4H-) of 1,2,4-triazoles are in rapid equilibrium. However, 1H-1,2,4-triazole is more stable than the 4H-1,2,4-triazole. Chemically, 1H-1,2,4-triazole shows both electrophilic and nucleophilic substitution reactions. Due to high electron density, electrophilic substitution occurs at nitrogen atoms only. Under mild reaction conditions, nucleophilic substitution occurs at both the ring carbon atoms. This is because both the ring carbon atoms are attached to two electronegative nitrogen atoms and become π-deficient, which makes them susceptible to nucleophiles.

7Huge applications, promising research directions, and lower molecular toxicity of various triazoles and their derivatives have promoted the researchers to design many synthetic strategies. Availability of reagents and simplicity of synthetic procedures justified the fact.

8In neoteric chemistry, the 1,2,3-triazole group is one of the most significant functional aromatic heterocyclic systems.

9The uncovering of the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) helps the inception of click chemistry and is mainly used as a unique tool to synthesize a wide variety of 1,4-disubstituted triazole compounds. CuAAC is well known for its inexpensive catalytic systems and generates highly regioselective products.

10utilized Huisgen 1,3-dipolar cycloaddition of terminal alkynes (1) with methyl 2-azidoacetate (2) in the presence of Cu(I) and obtained 1,4-disubstituted-1,2,3-triazole derivatives (3) in high yields at 25°C (Supplementary Figure S1B). The general Huisgen 1,3-dipolar cycloaddition reaction of azides with alkynes under heating conditions produces an equal mixture of 1,4- and 1,5-disubstituted isomers. However, the use of Cu(I) catalyst in such a one-pot reaction shows regioselectivity with the formation of only the 1,4-disubstituted isomer and is a model example of click chemistry. Encouragingly, many of the 1,4-disubstituted-1,2,3-triazoles (3) showed notable inhibitory activities against Src kinase, and hence could be effective in cancer treatment.

11A copper-catalyzed click reaction was used to prepare benzimidazole-linked 1,2,3-triazoles (6) (Supplementary Figure S1B). The key step involves the CuAAC reactions between aromatic azides (4) and n-propynylated benzimidazole (5) via a copper catalyst. In this method, the ligand is not necessary, and hence, the purification process of this reaction is very simple.

12Similarly, 1,3-dipolar cycloaddition of n-alkyl propargyl ethers (terminal alkynes) (7) with substituted azidoacetamide (8) furnished corresponding substituted 1,2,3-triazoles (9) in good yields (55–81%; Supplementary Figure S1C).

13In 2016, a metal-free three-component new protocol was reported for the direct and selective synthesis of 1,5-disubstituted-triazoles (13). In this approach, primary amines (10), enolizable ketones (11), and 4-nitrophenyl azide (12) in the acetic acid catalyst (30 mol%) are heated at 100°C in toluene (Supplementary Figure S2A).

14A straightforward, metal-free, and expandable click protocol for the preparation of 1-substituted-1,2,3-triazoles is reported. They used ethenesulfonyl fluoride (ESF) as a stable, the most perfect Michael acceptor, and an efficient acetylene surrogate. Thus, treatment of azide (14) with ESF in EtOAc under reflux condition furnished 1-substituted-1,2,3-triazole(s) (15) in good-to-excellent yield (Supplementary Figure S2B; ). However, the performance of the reaction at ambient temperature in benzene is unsuccessful.

15This approach is suitable for the synthesis of many drug and drug fragments with 1-substituted-1,2,3-triazole (e.g., chloramphenazole, triazolyl oseltamvir, triazolyl dapsone, etc.). In addition, a similar strategy is useful for the synthesis of 1-substituted-1H-1,2,3-triazole-4-sulfonyl fluorides (15a) by changing ESF to BESF (1-bromoethene-1-sulfonyl fluoride).

16Over the last decades, organocatalytic azide-carbonyl [3 + 2]-cycloaddition (OrgACC) reactions received significant attention. The versatility of such reactions is also applied in the synthesis of 1,2,3-triazoles via enamine/enolate-mediated organocatalysis. In this regard, a series of aliphatic and cyclic tertiary amines are extensively investigated, and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) was established as the most effective catalyst. Among different solvents, DMSO and chloroform are found as the best solvent for this DBU-catalyzed 1,3-dipolar cycloaddition reaction.

17In 2015, a group of researchers developed the application of DBU as a catalyst in organocatalytic [3 + 2] 1,3-dipolar cycloaddition between α,β-unsaturated esters and azides. This synthetic strategy is found to form regioselective 1,4-disubstituted-1,2,3-triazoles (16) in high yields. A highly important class of triazoles are found to be 1,4-disubstituted-1,2,3-triazoles. For example, ammonolysis of such triazole (16a) can form pharmaceutically important agents such as rufinamide (17; Supplementary Figure S2C).

18Later on, the same group successfully extended the aforementioned organocatalytic (DBU) strategy with β-keto amides (18) and obtained highly substituted 1,2,3-triazole-4-carboxamides (19a-z) in excellent yields with substituent regioselectivity at 1-, 4-, and 5-positions (Supplementary Figure S2D). They have also outlined the probable mechanism.

19Application of a similar strategy by the change of azide to imidazole sulfonyl azide with β-keto esters provides an efficient one-pot practical method for N-amino-triazole synthesis. As shown in Supplementary Figure S3A, hydrazine (21) was obtained from β-keto esters (20), which on treatment with imidazole sulfonyl azide catalyzed by DBU-furnished 1,2,3-triazoles (22) containing nitrogen atom at the 1-position. This simple protocol is found to be applicable to acyclic and cyclic 1,3-diones. In addition, the extra NH group at 1-position can form H-bond with many biological systems.

20Finally, the metal-free OrgACC reaction promoted by DBU in DMSO is found suitable for the preparation of functionally rich vinyl-/alkyl-/aryl-containing 1,2,3-triazoles under ambient conditions. It should be noted that the less reactive vinyl/alkyl/aryl azides could be successfully used in these reaction conditions. For example, cyclic enone (23) with vinyl azide (24; α-azidostyrene) catalyzed by DBU furnished the corresponding C/N-divinyl-1,2,3-triazole (25) (Supplementary Figure S3B). These C-vinyl- and N-vinyl-triazoles have many biological activities, including EP4 receptor antagonists, α-glycosidase inhibition, antitubercular, antimicrobial, tubulin inhibition, and anti-inflammatory properties.

21Since 2015, several researchers reported the applicability of ionic liquids (ILs) as a solvent and catalyst for the regioselective synthesis of 1,2,3-triazoles. The use of ILs as nontoxic benign solvents can improve the reaction rate and regioselectivity of the cycloaddition reaction. A simple bifunctional IL catalyst, namely, choline chloride-CuCl was found highly active for the [3 + 2] Huisgen cycloaddition in H2O. In a one-pot, three-component reaction among organic halide (26), NaN3, and terminal alkyne (27) with this IL catalyst formed 1,4-disubstituted-triazole (28) (Supplementary Figure S3C).

22In 2018, another group of researchers reported the application of 1-methyl pyridinium trifluoromethane sulfonate ([mPy]OTf) as an efficient and reusable homogenous IL catalyst in the eliminative azide–olefin cycloaddition (EAOC) reaction. Thus, the reaction between substituted azides (29) and nitroolefins (30a-n) catalyzed by [mPy]OTf/FeCl3 yielded 1,5-disubstituted-1,2,3-triazoles (31a-n) (Supplementary Figure S3D). The reaction proceeded in a very short reaction time with higher regioselectivity and the final products.

23Later on, the same authors applied this IL [mPy]OTf with H2O/Er(OTf)3, which matches with the anionic part of the IL and produces similar 1,5-disubstituted-triazoles. This catalyst system can be reused five times with a simple work-up procedure.

24In the next year, the same research group developed an IL-catalyzed novel synthetic route with 1,3-dipolar cycloaddition (Huisgen’s-concerted asynchronous) followed by base-promoted elimination (retro-aza-Michael) for the preparation of trisubstituted triazoles from aryl azides and enaminones. According to this strategy, stirring of a mixture of enaminone (32a-c) and azide (33a-g) (2 eq) with [mPy]OTf -water (5:0.5 v/v) and Et3N (2 eq) at 100°C formed the trisubstituted products (34a-p) with the regioselectivity at 1-, 4-, and 5-positions (Supplementary Figure S3E). Thus, this IL-promoted regioselectivity is different from the previously mentioned ionic liquid/iron (III) chloride method, which showed regioselectivity at 1- and 5-positions of the 1,2,3-triazole skeleton. For an in-depth understanding of the role of catalysts, a detailed comparison of different ILs and other catalysts used is also outlined.

25Recently, Cu(II) IL ([Bmim][CuCl3])–promoted regioselective preparation of 1,4-disubstituted-1,2,3-triazole is reported. The necessary IL [Bmim][CuCl3] is prepared from CuCl2 and 1-butyl-3-methylimidazolium chloride. The reaction of azide (35) with 1-alkyne (36) in the presence of catalyst [Bmim][CuCl3] and reducing agent ascorbic acid at room temperature yielded triazole (37) (Supplementary Figure S4A). Here, in situ generations of the active Cu(I)-IL from Cu(II)-IL by ascorbic acid advantageously facilitate the rapid formation of the product.

26Recently, microwave irradiation (MWI) was applied for the copper-catalyzed azide–alkyne cycloaddition (CuAAC) method. Thus, MWI of initially prepared 4-methyl-7-propargylated coumarin (terminal alkyne) (38) with various substituted azides (39) in sodium ascorbate and hydrated copper sulfate (CuSO4.5H2O) at 90°C undergoes 1,3-dipolar cycloaddition reaction and furnished 1,2,3-triazoles (40a-t) linked with coumarin at the C-4 position in 2–5 min with 97% isolated yield (Supplementary Figure S4B).

27Coumarin triazoles (40a-t) exhibited promising antibacterial activity compared to the standard drug, ciprofloxacin, and fungal pathogens. This observation is also supported by a higher binding affinity of (40) (−6.3 to −7.2 kcal/mol) than that of ciprofloxacin (−6.2 kcal/mol) with the gyrase enzyme.

28The change of CuSO4.5H2O to Zn(OAc)2 and H2O in the earlier MW-assisted CuAAC reaction also proceeds with similar regioselectivity (1,4-disubstituted products) and is considered an environmentally friendly inexpensive catalyst in neat water.

29A new and efficient catalyst-like monophosphine Cu(I) complex containing bis(pyrazolyl)methane (L1) (CuIL1PPh3) under ultrasonic (US) conditions was used in the three-component click reaction, and disubstituted 1,2,3-triazoles are formed. Thus, CuIL1PPh3 catalyzed a one-pot reaction of alkyl halide (41), sodium azide, and terminal alkyne (42) under US conditions in water-furnished 1,4-disubstituted-triazoles (43) (Supplementary Figure S4C). This CuIL1PPh3 catalyst is compatible with oxygen/water and triazoles (43a-l), which are formed in a shorter reaction time. The halo-aryl–substituted products are modified via Suzuki–Miyaura cross-coupling to add pharmacophore(s), which exhibited better binding affinity with the carbonic anhydrase-II enzyme.

30Due to the role as key skeletons of a plethora of biologically active molecules, several synthetic methods for 1,2,4-triazole synthesis were reported since 2015 along with many reviews. Some of the synthetic strategies such as Cu-catalyzed synthesis, base-catalyzed synthesis, MW-assisted methods, and miscellaneous methods are highlighted here based on synthetic convenience, diversity, novelty, and good yields (more synthetic 1,2,4-triazoles are mentioned in the Supplementary Material).

31In 2015, Cu catalyzed an efficient one-pot synthetic strategy described for symmetrically and unsymmetrically substituted 1,2,4-triazoles from hydroxylamine and nitriles in moderate yields. The strategy consists of intermolecular addition of hydroxylamine to the first nitrile to provide amidoxime followed by the reaction of the second nitrile in the presence of Cu and intramolecular cyclization to yield disubstituted triazole (44) (Supplementary Figure S5A). In the second step, sequential N–C and N–N bond formation occurs by dehydration.

32Base-catalyzed (ethanolic NaOH/KOH/NaHCO3) cyclization of acyl thiosemicarbazide (45a-c) under reflux condition paves easy access to the 3-aryl-5-mercapto-1,2,4-triazoles (46a-c) (Supplementary Figure S5B; ). Triazoles (46a-c) exhibited in vitro anticarcinogenic susceptibility against the breast cancer cell line (MDA-MB-231). In addition, 5-mercapto-1,2,4-triazoles (46a-c) can be used as a scaffold for the preparation of S-substituted triazoles with antiproliferative activities in colorectal cancer.

33Similarly, 5-mercapto-1,2,4-triazole with 4-amino skeleton (47) is shown to be extremely useful for the synthesis of fused triazolo–trizines 48 (; Supplementary Figure S5C). These compounds showed excellent antimicrobial and anti-inflammatory activities compared to commercial antibiotics.

34Microwave (MW) heating was used for condensation between t-butyl-1-cyanopiperazine carboxylate (49) and 2-fluorobenzohydrazide (50) in DMF at 120°C to produce the corresponding 3,5-disubstituted-1,2,4-triazole-based piperazine (51) (Supplementary Figure S6A). The cyclization proceeds with a high yield (>99%) and did not use any base. Triazole (51) was also converted into several amides and urea derivatives mostly under mild MW conditions.

35New spiro-type 1,2,4-triazoles (53) are prepared successfully from amidrazones (52) with cyclic ketones using p-toluenesulfonic acid (p-TSA) as the catalyst (; Supplementary Figure S6B). These spiro-triazoles possess marked antimicrobial activities and are comparable to tetracycline and fluconazole.

361,2,4-triazoles (54a-m) with pyrazole and thioether moieties (3,5-disubstituted) are reported. The synthesis was accomplished within six steps (Supplementary Figure S6C). Encouragingly, compounds (54a-m) exhibited fungicidal and herbicidal activities.

37In 2021, a multistep synthetic route for 2,3,4-trisubstituted-1,2,4-triazoles (56) was reported, where the key step involves the replacement of the ring oxygen of oxadiazole (55) by the addition of hydrazine hydrate (Supplementary Figure S6D). The biological screening and SAR of these trisubstituted derivatives indicated promising antimicrobial and anticancer activity against HCT116 cell lines. For anticarcinogenic studies, the N-amino-1,2,4-triazole-type compounds (56) are also converted into several new Schiff bases (57).

38The presence of the three nitrogen atoms in triazole structures afforded opportunities for a plethora of structural modification with the generation of novel therapeutically potential agents, which is different from other heterocyclic compounds. Thus, triazoles are a significant platform in medicinal chemistry and chemical biology, which play key roles in various biological mechanisms related to infections, cancer, convulsions, inflammation, neurodegeneration, and oxidative stress. Relatedly, many drugs are available in the market. However, the synthesis of newer triazoles is in a continuous process for uncovering unexplored and advanced pharmacological implications.

39Bioactive molecules with 1,2,3-triazole core nucleus have been proven to possess antibacterial (e.g., cefatrizine, Supplementary Figure S7), antifungal, herbicide, anticancer (e.g. carboxyamidotriazole or CAI) protease inhibitory, and antituberculosis activities. In search of novel modes of action, many novel 1,2,3-triazoles have been synthesized since 2015. As an instance, a group of researchers discovered that icotinib-1,2,3-triazole derivatives (58) (Supplementary Figure S7) exhibited remarkable inhibitory activity against indoleamine 2,3-dioxygenase 1 (IDO1) with very low IC50 values (0.37–2.50 μM), and hence are potential anticancer agents. These IDO1 inhibitors form a coordinate bond with the heme iron of IDO1.

40Triazoles linking nonsteroidal anti-inflammatory drugs (NSAIDs) and heterocyclic moiety such as 59 showed excellent inhibition against Gram-negative P. aeruginosa with anticancer properties (COLO-205 and HOP-62 cell-lines). Again, 1,2,3-triazoles (60) with short nonpolar alkyl or alkynyl substituents at 1,4 positions showed promising soil nitrification inhibition (pH 7.3). These triazoles can keep the effectiveness of existing nitrogen fertilizers by inhibiting nitrification, especially at elevated soil temperatures.

41In the last couple of years, several substituted 1,2,3-triazoles were investigated for their efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and most of them are based on in silico analyses. For example, combined 1,2,3-triazole and tetrazole moieties as in (61) (Supplementary Figure S7) are found to inhibit the main protease (MPRO, PDB ID: 6LU7) of SARS-CoV-2 having higher ligand–target interactions. Several functionalized 1,2,3-triazole derivatives (62) also showed good binding affinities (−6.0 to −8.8 kcal/mol) against the same protease 6LU7, and 1,2,3-triazoles (63) conjugated with quinolone also showed high potency against MPRO 6LU7. The antiviral results of (63) are also supported by their IC50 values (0.060–0.204 mM).

421,2,3-triazole–based Schiff bases 64 (Supplementary Figure S7) showed considerable binding affinities (−7.4 to −9.1 kcal/mol) with 7BQY, indicating their potential prospect as therapeutics for COVID-19 (Supplementary Figure S7).

43Many 1,2,4-triazole-derived drugs are used as antifungal, herbicidal, antiviral, and catalase inhibitors. Very recently, mefentrifluconazole was introduced to the European market as an effective fungicide. Several 1,2,4-triazoles such as (65a-b) (Supplementary Figure S7) are potent against Middle East respiratory syndrome coronavirus (MERS-CoV) helicase. The experimental (IC50 = 8.9–12.4 μM L−1) and in silico docking study indicated nsp13 as the most active binding site.

44For more information about the biological significance of triazoles, please refer to the Supplementary File.

45The core triazole ring structures with higher aromatic stabilization energy are modified for improving solubility and selectivity with the interacting binding site of the enzyme and acted as linkers among various pharmacophores. Thus, they have been shown to play a vital role in a wide range of biological activities, including fragment-based drug design, biomolecular mimetics, and bioorthogonal methodologies. In addition to the available triazole drugs, researchers are engaged to explore and develop new scaffolds based on triazole cores with huge applications in biomedical and biotechnology fields. In the present review, structural features, recent synthetic developments, and new biological applications of triazoles are highlighted, which might facilitate in-depth understanding and further development/discovery of these compounds.