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Communication

Synthesis of 1,2,4-Triazole-3-Thiol Derivatives from Thiosemicarbazides and Carboxylic Acids Using Polyphosphate Ester

by
Bogdan A. Tretyakov
1,
Viktoria I. Tikhonova
1,2,
Svyatoslav Y. Gadomsky
1,* and
Nataliya A. Sanina
1
1
Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, Chernogolovka 142432, Russia
2
Moscow Center for Advanced Studies, 20 Kulakova Str., Moscow 123592, Russia
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(22), 4422; https://doi.org/10.3390/molecules30224422 (registering DOI)
Submission received: 1 October 2025 / Revised: 11 November 2025 / Accepted: 13 November 2025 / Published: 16 November 2025
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Characterization and Biological Evaluation)
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Abstract

Conditions have been established for the direct reaction of thiosemicarbazides with carboxylic acids in the presence of polyphosphate ester (PPE) to synthesize 1,2,4-triazole-3-thiol derivatives. The synthesis involves two consecutive steps: (i) acylation of the thiosemicarbazide with a carboxylic acid in chloroform in the presence of PPE at 90 °C using a hydrothermal reaction vessel, followed by (ii) cyclodehydration of the acylation product by treatment with an aqueous alkali solution. Using this new synthetic approach, 15 derivatives of 1,2,4-triazole-3-thiol were obtained, five of which were synthesized for the first time. The structures of the synthesized compounds were confirmed by NMR spectroscopy and mass spectrometry.

1. Introduction

Triazoles, in general, hold a special place in modern coordination and medicinal chemistry research [1,2,3,4]. This is also true for such a specific type of triazoles as 1,2,4-triazole-3-thiol derivatives. The biological activity of these compounds has been demonstrated against a range of important targets (Figure 1), though this list is not exhaustive and focuses on the most studied areas. Table 1 shows that 1,2,4-triazole-3-thiols are promising agents for anticancer therapy [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27], as well as for treating diabetes [28,29,30,31,32,33], inflammatory [34,35,36,37,38], neurological [30,39,40,41,42,43,44,45,46,47,48], and respiratory [35,49,50,51] disorders, and bacterial infections [52,53,54,55,56,57,58]. In addition to their action on molecular targets, there are also examples of antibacterial and antifungal activity [13,59,60,61,62,63,64,65,66] of the discussed triazoles against a range of common strains (Table 2), including pathogens of such dangerous diseases as tuberculosis [63,64,65], pneumonia [60,66], and candidiasis [13,59,60,61].
All literature-described approaches to the synthesis of 1,2,4-triazole-3-thiols can be divided into two main types, which are presented as a simplified scheme in Figure 2. The first approach (Figure 2), which involves the reaction of hydrazides with isothiocyanates, serves as the basis for synthesis in most of the works mentioned above [8,9,10,12,13,14,17,18,19,21,22,23,27,30,35,36,37,38,39,41,42,43,46,50,56,58,59,60,61,62,64,65,66]. Thus, in the context of the reviewed literature, this synthetic route is the most prevalent. It is important to note that the first reaction in Figure 2 is presented in a simplified form, as it is not entirely accurate for R2 = H. In this case, the reaction is carried out not with thiocyanic acid, but with its salts, i.e., with thiocyanates [9,12,56].
The second approach (Figure 2) involves the acylation of thiosemicarbazide derivatives (with a pre-activated carboxyl group) followed by cyclodehydration under alkaline conditions.
Although this approach is encountered much less frequently in the aforementioned sources [16,20,24,46,47,52,60,63], it offers significantly greater diversity in terms of experimental conditions, which primarily depend on the method of carboxyl group activation. In the vast majority of cases, such reactions have been performed using acid chlorides [24,46,52,60,63]. However, there are also examples employing activating agents such as propylphosphonic anhydride (T3P) [16], HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) [20] and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) [47]. The fact that acid chlorides are most commonly used in the second approach (Figure 2) suggests a high relevance for research aimed at finding more accessible conditions for the acylation of thiosemicarbazides.
We have previously shown [67] that in the presence of polyphosphate ester (PPE) the reaction of carboxylic acids with thiosemicarbazide leads to the formation of 1,3,4-thiadiazol-2-amine derivatives. Furthermore, it has been experimentally demonstrated [67], that this synthesis proceeds in two stages with the formation of an intermediate acylation product (Figure 3, main direction), which is a compound that could also be utilized for the synthesis of 1,2,4-triazole-3-thiols. However, how to realize the potential of PPE for the synthesis of the target triazoles remained unclear until now. Therefore, the present study was aimed at finding optimal conditions to shift the course of the reaction between carboxylic acids and thiosemicarbazide in the presence of PPE towards the formation of 1,2,4-triazole-3-thiols (Figure 3).

2. Results and Discussion

It was previously shown [67] that the reaction conditions for thiosemicarbazide with benzoic acid in the presence of PPE can be optimized to yield 2-benzoylhydrazine-1-carbothioamide as the main product. However, the universality of these conditions and their applicability to substituted thiosemicarbazides remained unclear. Therefore, reactions of benzoic acid with thiosemicarbazides bearing different substituents (aliphatic and aromatic) were carried out under conditions as close as possible to those described earlier [67] (Scheme 1). Despite an observed trend of decreasing yield (when moving from unsubstituted to aromatic thiosemicarbazide, see descriptions 1a–c in the Supplementary Materials), the acylation products were isolated and characterized in all three cases. Thus, the principal applicability of PPE for the acylation of various thiosemicarbazides was demonstrated.
The reaction mechanism is no less important. We previously suggested [67] that the reaction proceeds via the intermediate formation of a thiosemicarbazide salt with the carboxylic acid (Scheme 1). To test this hypothesis, we made several attempts to synthesize and isolate the thiosemicarbazide salt with benzoic acid in pure form, intending to subsequently treat it with a solution of PPE in chloroform. However, all attempts to obtain the target salt in aqueous-alcoholic mixtures, as well as in mixtures of water with DMSO and DMF, yielded negative results—only mixtures of the starting compounds could be isolated instead of the target salt. It is quite possible that if the target salt is formed, it hydrolyzes immediately in the presence of even trace amounts of water. Indirect confirmation of this is the following observed feature, which was later implemented in the triazole synthesis method described below: the use of pre-dried chloroform as a solvent significantly increases the yield of the target reaction. Another indirect confirmation of the proposed mechanism (Scheme 1) is the invalidity of a potential alternative viewpoint, suggesting the involvement of a mixed anhydride formed from the carboxylic acid and PPE. The desired acylation reaction does not proceed if the thiosemicarbazide is added to a pre-prepared mixture of the carboxylic acid and PPE (i.e., if the presumed mixed anhydride is allowed to form). The only possible way to achieve the discussed reaction is to pre-mix the starting compounds in dry form followed by treatment with a solution of PPE.
As a result of the search for universal acylation conditions, the following important features were discovered, which later formed the basis of the described method for the synthesis of 1,2,4-triazole-3-thiols: 1. Chloroform is the most universal solvent compared to dichloromethane, chlorobenzene, toluene, ethyl acetate, DMF, and DMSO (in all other solvents, the reaction between benzoic acid and thiosemicarbazide either did not proceed or gave a negligibly low yield of the target compound); 2. During the acylation reaction, the following sequential change in the appearance of the reaction mixture is typically observed: the mixture first becomes homogeneous, followed by the gradual formation of a precipitate of the acylation product (however, in some cases, the product precipitate could form over a week or more); 3. The target 1,2,4-triazole-3-thiols are much easier to isolate in pure form compared to the intermediate acylation products, as they can be readily converted into a water-soluble form as potassium salts (thus, the target product can be separated from impurities by treating the aqueous solution with activated charcoal).
Considering the features listed above, it was decided to carry out the reaction of carboxylic acids with thiosemicarbazides in two immediate steps (Scheme 2), using a hydrothermal reaction vessel for the first stage. As shown in Scheme 2, the acylation of thiosemicarbazide may form a thiadiazole side product, aligning with the main reaction pathway in the presence of PPE (Figure 3). The two-step method capitalizes on the insolubility of the resulting 1,3,4-thiadiazol-2-amines in alkaline medium to easily separate them from the target 1,2,4-triazole-3-thiols in the second stage. This bypasses the need for intermediate isolation, greatly streamlining the synthesis. The use of a hydrothermal reactor allowed for an increase in the reaction temperature without changing the solvent and accelerated the precipitation of the acylation product from the reaction mixture.
Given the aforementioned problem of thiadiazole formation as a competitive product, it is also important to discuss the spectral distinctions between 1,2,4-triazole-3-thiol derivatives and their functional isomers, 1,3,4-thiadiazol-2-amines. Figure 4 shows a comparison of the 1H NMR spectra of 5-phenyl-4H-1,2,4-triazole-3-thiol and 5-phenyl-1,3,4-thiadiazol-2-amine. A significant difference is evident (Figure 4) in the chemical shift regions for the protons of the triazole and thiadiazole rings. Specifically, the N-H and S-H protons of the triazole resonate at a much lower field (13–14 ppm) compared to the amino group signal of the thiadiazole, which appears in the aromatic region (Figure 4). Thus, it is clear that 1H NMR spectroscopy alone is sufficient for the reliable structural identification of the isolated products.
Table 3 presents the results obtained from the implementation of Scheme 2. It can be seen (Table 3) that the yield values are not high; however, it is necessary to consider that these data are calculated for individually isolated compounds after a two-step synthesis. But the most important point to emphasize is the discovered difference between syntheses 2a–h and 2i–m. In the first case (2a–h), the reaction in the hydrothermal reactor resulted in the formation of an easily separable precipitate of the intermediate, whereas in the case of carboxylic acids with nitrogen-containing heterocycles (2i–m), a resin-like mass was formed instead of a precipitate. It is quite probable that in the case of 2i–m, we observed the formation of a polymeric salt between the quaternized nitrogen of the intermediate (acylated thiosemicarbazide) and the generated residues of polyphosphoric acid.
Compounds 2n and 2o deserve special attention; their yields are not listed in Table 3. In these cases, using the exact same “hydrothermal” stage conditions as for 2a–m led to a significant increase in the conversion depth; i.e., the reactions did not stop at the acylation stage but proceeded to the next stage of cyclo-dehydration, forming products 3n and 3o (Figure 5). It is noteworthy that in the attempt to synthesize 2n, after the first stage (Scheme 2), only a trace amount of precipitate was observed (unlike the very similar reactions 2a–h), and product 3n was isolated from the remaining chloroform solution of the reaction mixture. Regarding the attempt to synthesize 2o, similarly to 2i–m, a resin-like mass was observed after the “hydrothermal” stage, from which product 3o was isolated. This resin formation is most likely associated with the reversible binding of the product’s hydroxyl group with residues of PPE or the forming polyphosphoric acid.
Despite the fairly diverse set of carboxylic acids used (Table 3), the obtained data are somewhat contradictory, making it difficult to identify any unambiguous correlation between the structure of the carboxylic acid and the yield of the target product. One possible reason for this variation in yields could be the difference in solubility of the acylation products in the reaction mixture: if the solubility of intermediate 1 is low, it precipitates at the first stage without undergoing further cyclodehydration to the thiadiazole. Based on this, it can be assumed that modifying the conditions of the “hydrothermal” stage could influence the yield of the target compounds. To test this hypothesis, we conducted additional attempts to synthesize 2n and 2o by varying the conditions of the first stage. In a new attempt to synthesize 2n, the reaction time, amount of chloroform, and PPE were significantly reduced. This indeed led to the formation of a precipitate (analogous to syntheses 2a–h). However, upon investigating the structure of the isolated product (and the product of its subsequent transformation under alkaline conditions), it was found that under the new conditions, the reaction proceeds according to Scheme 3, yielding products 4 and 5.
It is worth noting that the mechanism of formation of product 4 is unlikely to be related to the presence of PPE, as a similar conversion of phenylthiosemicarbazide occurs without dehydration (furthermore, the formation of 4 was observed when the amount of PPE was reduced). It is more probable that the observed effect is associated with the specific nature of 4-phenylthiosemicarbazide, which under certain conditions can convert into compound 4 [68]. Thus, it is evident that the reaction with 4-phenylthiosemicarbazide can be further complicated by the potential formation of product 4, which may ultimately affect the yield of the target compounds 2.
An attempt to carry out the synthesis of 2o under the conditions of Scheme 3 did not yield any significant results (TLC analysis showed that after 4 h, the reaction mixture contained 3o and the starting materials). A fundamentally different outcome was achieved by replacing chloroform with ethyl acetate as the solvent (Scheme 4). The successful implementation of Scheme 4 and the isolation of 2o provide indirect confirmation of the hypothesis regarding the influence of the acylation product’s solubility in the reaction mixture. However, applying ethyl acetate to the synthesis of 2n resulted in a homogeneous and difficult-to-separate reaction mixture, demonstrating the need to optimize the solvent for each specific structure and further indirectly confirming the importance of the solubility factor for a successful synthesis.
The practical significance of the proposed synthetic method for 1,2,4-triazole-3-thiols becomes evident in cases where the synthesis of the requisite hydrazides for the classical isothiocyanate-based approach is challenging or requires specific, non-standard conditions. A prime example of this problem is the synthesis of compound 2p (Scheme 5) starting from triazolyl propanoic acid.
We found that the reaction of methyl ester 6 with hydrazine in ethanol (Scheme 5) or isopropanol (detailed procedures are provided in the Supplementary Materials) does not yield the target hydrazide, even after 48 h. It is noteworthy that a structurally similar compound, 3-(1H-benzotriazol-1-yl)propanehydrazide, forms without any issues under the conditions shown in Scheme 5 [69]. The application of thionyl chloride, according to method [63], for the synthesis of 2p was also unsuccessful, as the formation of a complex, difficult-to-separate mixture of by-products made the isolation of the target compound virtually impossible. In contrast, the reaction of triazolyl propanoic acid with thiosemicarbazide under the conditions developed for 2i–m allowed for the straightforward isolation of compound 2p in pure form (Scheme 5). It is important to emphasize that the aforementioned experiment does not prove the absolute impossibility of synthesizing the hydrazide or the acid chloride of 3-(1H-1,2,4-triazol-1-yl)propanoic acid. Rather, it indicates that finding the optimal conditions for these intermediates would require a separate investigation, distinct from classical approaches. Therefore, under the current circumstances, the method described in this work represents the optimal pathway for the laboratory synthesis of compound 2p.

3. Materials and Methods

Starting materials. Commercial reagents (purity ≥ 97%) from Sigma-Aldrich (Steinheim, Germany) and Alladin Scientific (Shanghai, China) were used as starting materials. 1H-Benzotriazole-1-propanoic acid was prepared according to the procedure reported in [70]. 3-(1H-1,2,4-triazol-1-yl)propanoic acid was prepared according to the procedure reported in [71]. Polyphosphate ester was synthesized as described in [72].
Equipment. The following equipment was used for analysis: a Finnigan MAT INCOS 50 mass spectrometer (Finnigan Instrument Corporation, Bremen, Germany), a Bruker DRX-500 spectrometer (Bruker, Karlsruhe, Germany), and a Vario MICRO cube CHNS analyzer (Elementar Analysensysteme GmbH, Langenselbold, Germany). Synthesis of compounds 2 and 3 was performed using a 10 mL hydrothermal reaction vessel (PTFE with a stainless-steel jacket, Xi’an Taikang Biotechnology Co., Ltd., Xi’an, China).
General procedure for the synthesis of 1a–c. Benzoic acid (8.2 mmol) and thiosemicarbazide (8.2 mmol) were thoroughly mixed with a spatula in a 10 mL vial. Chloroform (6 mL) was added to the mixture, and the suspension was stirred at room temperature for 5 min. Subsequently, PPE (1.5 g) was added to the reaction mixture, which was stirred at 64 °C for 3 h and then cooled to room temperature. Precipitation occurred within 24 h. The resulting precipitate was filtered off, washed with chloroform and a water (90%)/methanol (10%) mixture.
General procedure for the synthesis of 2a–m. A carboxylic acid (8.2 mmol) and thiosemicarbazide (8.2 mmol) were thoroughly mixed with a spatula in a 10 mL hydrothermal reaction vessel. Dry chloroform (4 mL) and a stir bar were added to the mixture. The open vessel was placed on a magnetic stirrer. Then, PPE (1.5 g) was added to the reaction mixture under stirring, the vessel was sealed, and the jacket temperature was maintained at 90 °C for 11 h.
Isolation of 2a–h. The formed precipitate was filtered off, washed with chloroform, and suspended in water (15 mL). A 2 M KOH solution was added to adjust the pH to 9–10. The resulting mixture was stirred at 90 °C for 9 h, maintaining the pH at ~9–10 by periodic addition of 2 M KOH. Upon completion, any undissolved precipitate (except for 2e) was discarded. The filtrate was treated with activated charcoal (~80 mg) and acidified with 0.5 M HCl to pH ~2. The resulting precipitate was filtered off and washed with a water (90%)/methanol (10%) mixture. In the case of 2e, after 9 h of alkaline treatment, no significant dissolution of the precipitate was observed. Therefore, the precipitate was filtered off, dissolved in methanol (40 mL), and acidified with 0.5 M HCl to pH ~2. The formed precipitate was filtered off and washed with a water (90%)/methanol (10%) mixture.
Isolation of 2i–m. The primary difference from the procedure for 2a–h is that the reaction in the presence of PPE yields a resin-like mass instead of a precipitate. This mass was separated from chloroform by decantation, transferred into water (15 mL), and the subsequent steps were identical to those described for 2a–h.
Isolation of 3n from the reaction mixture targeting compound 2n. The resulting mixture was evaporated. The residue was mixed with water (15 mL), and a 2 M KOH solution was added to adjust the pH to 9–10. The mixture was stirred at 70 °C for 1 h. The formed precipitate was filtered off and washed with isopropyl alcohol (2 × 15 mL) and methanol (2 × 15 mL).
Isolation of 3o from the reaction mixture targeting compound 2o. The formed resin-like mass was separated from the chloroform residue and transferred into water (15 mL). A 2 M KOH solution was added to adjust the pH to 9–10, and the mixture was stirred at 80 °C for 2 h. Subsequently, the pH was adjusted to 6 by adding 0.5 M HCl. The precipitate was filtered off and washed with a water (90%)/methanol (10%) mixture.
Synthesis of 4 by the reaction targeting compound 2n. Phenylpropanoic acid (1.23 g) and 4-phenylthiosemicarbazide (1.37 g) were thoroughly mixed with a spatula in a 10 mL hydrothermal reaction vessel. Dry chloroform (2 mL) and a stir bar were added to the mixture. The open vessel was placed on a magnetic stirrer. Then, PPE (0.85 g) was added to the reaction mixture under stirring, the vessel was sealed, and the jacket temperature was maintained at 75 °C for 4 h. The formed precipitate was filtered off and washed with chloroform. Yield: 0.48 g (38%, based on the stoichiometry of formation of 4).
Synthesis of 5. A mixture of N1,N2-diphenylhydrazine-1,2-dicarbothioamide 4 (0.3 g) and KOH (0.15 g) in water (15 mL) was stirred at 90 °C for 4 h. The reaction mixture was then cooled to room temperature and acidified with HCl to pH ~6. The resulting precipitate was filtered off, washed with water and a water (90%)/methanol (10%) mixture. Yield: 0.19 g (71%).
Synthesis of 2o. 4-Hydroxybenzoic acid (1.13 g) and thiosemicarbazide (0.75 g) were thoroughly mixed with a spatula in a 10 mL hydrothermal reaction vessel. Dry ethyl acetate (2 mL) and a stir bar were added to the mixture. The open vessel was placed on a magnetic stirrer. Then, PPE (0.85 g) was added to the reaction mixture under stirring, the vessel was sealed, and the jacket temperature was maintained at 75 °C for 4 h. The resulting reaction mixture was transferred into ethyl acetate (50 mL) and treated in an ultrasonic bath for 30 min, yielding three fractions: an ethyl acetate solution, a colorless precipitate, and a resin-like mass (the resin was separated by decantation and discarded). The obtained precipitate was filtered off, washed with ethyl acetate, and treated with an aqueous alkali solution according to the procedure described above (see “Isolation of 2a–h”). Yield: 0.64 g (40%).
Synthesis of 2p. The synthesis and isolation of the product were carried out according to the general procedure described for compounds 2i–m, with a single modification: the resulting precipitate was additionally washed with acetone (3 × 20 mL).
Compounds 2e, 2k, 2l, 2m and 2p were obtained for the first time. The following compounds were described previously: 1a [73], 1b [74], 1c [75], 2a [27], 2b [74], 2c [76], 2d [77], 2f [78], 2g [79], 2h [80], 2i [81], 2j [82], 2o [74], 3n [83], 3o [84], 4 [68], 5 [85], 6 [86]. Spectral data are provided in the Supplementary Materials.

4. Conclusions

For the first time, the possibility of synthesizing 1,2,4-triazole-3-thiol derivatives via a direct reaction of thiosemicarbazides with carboxylic acids using polyphosphate ester (PPE) has been demonstrated. The synthesis is carried out in two stages: (i) acylation of the thiosemicarbazide with carboxylic acid in chloroform in the presence of PPE, followed by (ii) cyclodehydration of the resulting acylation product by treatment with an aqueous alkali solution. It was shown that the use of a hydrothermal reaction vessel is optimal for the acylation stage, as the simultaneous increase in temperature and pressure simplifies the isolation of the intermediate acylation product for the second synthesis stage. The found conditions for the acylation stage can be considered nominally optimal; however, it was demonstrated that in some cases, the process can proceed further to form thiadiazoles. This effect is indirectly shown to be primarily associated with the solubility of the acylation product in the reaction mixture: to halt the reaction at the acylation stage and avoid thiadiazole formation, a solvent system most conducive to the precipitation of the acylation product must be selected (i.e., optimal conditions must be determined individually for each reaction to maximize the target product yield). Furthermore, it was shown that the use of a hydrothermal reaction vessel significantly reduces the amount of PPE required for the synthesis of thiadiazoles compared to previously reported procedures [67]. Additionally, it was demonstrated that PPE can be used for the acylation of thiosemicarbazides with 4-hydroxybenzoic acid without prior protection of the hydroxyl group, unlike the method described, for example, in [84]. Thus, the combination of PPE and a hydrothermal reactor has been shown to be highly effective for conducting dehydration and cyclodehydration reactions, a strategy that could find application not only in the synthesis of triazoles or thiadiazoles but also in the synthesis of other heterocycles via reactions involving hydrazides, amides, diacyl hydrazines, amino acids, etc.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30224422/s1. Description of spectral data, and NMR and mass spectra images of the obtained compounds (Figures S1–S37), along with an additional synthesis procedure for compound 6 and a description of attempts to carry out the reaction of 6 with hydrazine hydrate.

Author Contributions

Conceptualization, S.Y.G. and N.A.S.; methodology, S.Y.G.; formal analysis, S.Y.G. and B.A.T.; investigation, B.A.T., V.I.T. and S.Y.G.; data curation, B.A.T.; writing—original draft preparation, S.Y.G. and B.A.T.; writing—review and editing, S.Y.G.; visualization, S.Y.G. and V.I.T.; supervision, N.A.S.; project administration, N.A.S. All authors have read and agreed to the published version of the manuscript.

Funding

The work has been performed with the financial support of RSF grant N 25-73-20036 https://ias.rscf.ru/user/doc/a.w.p.2025.108.main/10522281 (accessed on 1 October 2025).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Aman, K.; Seema, D.; Sanjeev, K.; Kashmiri, L. Recent advancements in the multifaceted biomedical efficacy of triazole based metal complexes. Coord. Chem. Rev. 2025, 536, 216675. [Google Scholar] [CrossRef]
  2. Isern, J.A.; Carlucci, R.; Labadie, G.R.; Porta, E.O.J. Progress and Prospects of Triazoles in Advanced Therapies for Parasitic Diseases. Trop. Med. Infect. Dis. 2025, 10, 142. [Google Scholar] [CrossRef]
  3. Glomb, T.; Minta, J.; Nowosadko, M.; Radzikowska, J.; Świątek, P. Search for New Compounds with Anti-Inflammatory Activity Among 1,2,4-Triazole Derivatives. Molecules 2024, 29, 6036. [Google Scholar] [CrossRef]
  4. Ameziane El Hassani, I.; Rouzi, K.; Ameziane El Hassani, A.; Karrouchi, K.; Ansar, M. Recent Developments Towards the Synthesis of Triazole Derivatives: A Review. Organics 2024, 5, 450–471. [Google Scholar] [CrossRef]
  5. Magnaghi, P.; D’Alessio, R.; Valsasina, B.; Avanzi, N.; Rizzi, S.; Asa, D.; Gasparri, F.; Cozzi, L.; Cucchi, U.; Orrenius, C.; et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat. Chem. Biol. 2013, 9, 548–556. [Google Scholar] [CrossRef] [PubMed]
  6. Casciuc, L.; Horvath, D.; Gryniukova, A.; Tolmachova, K.A.; Vasylchenko, O.V.; Borysko, P.; Moroz, Y.S.; Bajorath, J.; Varnek, A. Pros and cons of virtual screening based on public “Big Data”: In silico mining for new bromodomain inhibitors. Eur. J. Med. Chem. 2019, 165, 258–272. [Google Scholar] [CrossRef] [PubMed]
  7. Aouad, M.R.; Almehmadi, M.A.; Albelwi, F.F.; Teleb, M.; Tageldin, G.N.; Abu-Serie, M.M.; Hagar, M.; Rezki, N. Targeting the interplay between MMP-2, CA II and VEGFR-2 via new sulfonamide-tethered isomeric triazole hybrids; Microwave-assisted synthesis, computational studies and evaluation. Bioorg. Chem. 2022, 124, 105816. [Google Scholar] [CrossRef]
  8. Malebari, A.M.; Ibrahim, T.S.; Salem, I.M.; Salama, I.; Khayyat, A.N.; Mostafa, S.M.; El-Sabbagh, O.I.; Darwish, K.M. The Anticancer Activity for the Bumetanide-Based Analogs via Targeting the Tumor-Associated Membrane-Bound Human Carbonic Anhydrase-IX Enzyme. Pharmaceuticals 2020, 13, 252. [Google Scholar] [CrossRef] [PubMed]
  9. Vats, L.; Kumar, R.; Bua, S.; Nocentini, A.; Gratteri, P.; Supuran, C.T.; Pawan, K.; Sharma, P.K. Continued exploration and tail approach synthesis of benzenesulfonamides containing triazole and dual triazole moieties as carbonic anhydrase I, II, IV and IX inhibitors. Eur. J. Med. Chem. 2019, 183, 111698. [Google Scholar] [CrossRef]
  10. Khan, F.M.; Abbasi, M.A.; Rehman, A.U.; Siddiqui, S.Z.; Butt, A.R.S.; Raza, H.; Zafar, A.; Shah, S.A.A.; Shahid, M.; Seo, S.-Y. Convergent synthesis of carbonic anhydrase inhibiting bi-heterocyclic benzamides: Structure–activity relationship and mechanistic explorations through enzyme inhibition, kinetics, and computational studies. J. Heterocycl. Chem. 2021, 58, 1089–1103. [Google Scholar] [CrossRef]
  11. Pitucha, M.; Janeczko, M.; Klimek, K.; Fornal, E.; Wos, M.; Pachuta-Stec, A.; Ginalska, G.; Kaczor, A.A. 1,2,4-Triazolin-5-thione derivatives with anticancer activity as CK1γ kinase inhibitors. Bioorg. Chem. 2020, 99, 103806. [Google Scholar] [CrossRef]
  12. Zhou, W.; Xu, C.; Dong, G.; Qiao, H.; Yang, J.; Liu, H.; Ding, L.; Sun, K.; Zhao, W. Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction. Eur. J. Med. Chem. 2021, 217, 113326. [Google Scholar] [CrossRef]
  13. Hassan, G.S.; El-Messery, S.M.; Al-Omary, F.A.M.; Al-Rashood, S.T.; Shabayek, M.I.; Abulfadl, Y.S.; Habib, E.-S.E.; El-Hallouty, S.M.; Fayad, W.; Mohamed, K.M.; et al. Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study. Eur. J. Med. Chem. 2013, 66, 135–145. [Google Scholar] [CrossRef]
  14. Zhang, X.; Chen, F.; Petrella, A.; Chacón-Huete, F.; Covone, J.; Tsai, T.-W.; Yu, C.-C.; Forgione, P.; Kwan, D.H. A High-Throughput Glycosyltransferase Inhibition Assay for Identifying Molecules Targeting Fucosylation in Cancer Cell-Surface Modification. ACS Chem. Biol. 2019, 14, 715–724. [Google Scholar] [CrossRef]
  15. Vergani, B.; Sandrone, G.; Marchini, M.; Ripamonti, C.; Cellupica, E.; Galbiati, E.; Caprini, G.; Pavich, G.; Rocchio, G.P.; Lattanzio, M.; et al. Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation. J. Med. Chem. 2019, 62, 10711–10739. [Google Scholar] [CrossRef]
  16. Vergani, B.; Caprini, G.; Fossati, G.; Lattanzio, M.; Marchini, M.; Pavich, G.; Pezzuto, M.; Ripamonti, C.; Sandore, G.; Steinkühler, C.; et al. Selective HDAC6 Inhibitors. International Patent WO 2018/189340 A1, 18 October 2018. [Google Scholar]
  17. Du, Z.; Foley, K. Method for Treating Proliferative Disorders Associated with Protooncogene Products. International Patent WO 2007139951 A2, 25 May 2007. [Google Scholar]
  18. Ying, W.; James, D.; Zhang, S.; Przewloka, T.; Chae, J.; Chimmanamada, D.U.; Lee, C.-W.; Kostik, E.; Ng, H.P.; Foley, K.; et al. Triazole Compounds That Modulate HSP90 Activity. United States Patent US 8901308 B2, 2 December 2014. [Google Scholar]
  19. Alsehli, M.; Aljuhani, A.; Ihmaid, S.K.; El-Messery, S.M.; Othman, D.I.A.; El-Sayed, A.-A.A.A.; Ahmed, H.E.A.; Rezki, N.; Aouad, M.R. Design and Synthesis of Benzene Homologues Tethered with 1,2,4-Triazole and 1,3,4-Thiadiazole Motifs Revealing Dual MCF-7/HepG2 Cytotoxic Activity with Prominent Selectivity via Histone Demethylase LSD1 Inhibitory Effect. Int. J. Mol. Sci. 2022, 23, 8796. [Google Scholar] [CrossRef] [PubMed]
  20. King, B.W.; Bell, B.; Sheppeck, J.; Gilmore, J.L. Triazolone and Triazolethione Derivatives as Inhibitors of Matrix Metalloproteinases and/or TNF-α Converting Enzyme. International Patent WO 2004032846 A2, 11 July 2006. [Google Scholar]
  21. Leyla Yurttaş, L.; Evren, A.E.; Kubilay, A.; Temel, H.E. Synthesis of New 1,2,4-Triazole Derivatives and Investigation of Their Matrix Metalloproteinase-9 (MMP-9) Inhibition Properties. Acta Pharm. Sci. 2021, 59, 215–232. [Google Scholar] [CrossRef]
  22. Youssef, M.F.; Nafie, M.S.; Salama, E.E.; Boraei, A.T.A.; Gad, E.M. Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells. ACS Omega 2022, 7, 45665–45677. [Google Scholar] [CrossRef]
  23. Boraei, A.T.A.; Singh, P.K.; Sechi, M.; Satta, S. Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation. Eur. J. Med. Chem. 2019, 15, 11162. [Google Scholar] [CrossRef] [PubMed]
  24. Munkuev, A.A.; Mozhaitsev, E.S.; Chepanova, A.A.; Suslov, E.V.; Korchagina, D.V.; Zakharova, O.D.; Ilina, E.S.; Dyrkheeva, N.S.; Zakharenko, A.L.; Reynisson, J.; et al. Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments. Molecules 2021, 26, 3128. [Google Scholar] [CrossRef] [PubMed]
  25. Shultz, M.D.; Kirby, C.A.; Stams, T.; Chin, D.N.; Blank, J.; Charlat, O.; Cheng, H.; Cheung, A.; Cong, F.; Feng, Y.; et al. [1,2,4]Triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: Antagonists of the Wnt Pathway That Inhibit Tankyrases 1 and 2 via Novel Adenosine Pocket Binding. J. Med. Chem. 2012, 55, 1127–1136. [Google Scholar] [CrossRef]
  26. Yu, M.; Yang, Y.; Sykes, M.; Wang, S. Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer. J. Med. Chem. 2022, 65, 5244–5273. [Google Scholar] [CrossRef]
  27. Shahzad, S.A.; Yar, M.; Khan, Z.A.; Shahzadi, L.; Naqvi, S.A.R.; Mahmood, A.; Ullah, S.; Shaikh, A.J.; Sherazi, T.A.; Bale, A.T.; et al. Identification of 1,2,4-triazoles as new thymidine phosphorylase inhibitors: Future anti-tumor drugs. Bioorg. Chem. 2019, 85, 209–220. [Google Scholar] [CrossRef] [PubMed]
  28. Balba, M.; El-Hady, N.A.; Taha, N.; Rezki, N.; El Ashry, E.S.H. Inhibition of α-glucosidase and α-amylase by diaryl derivatives of imidazole-thione and 1,2,4-triazole-thiol. Eur. J. Med. Chem. 2011, 46, 2596–2601. [Google Scholar] [CrossRef] [PubMed]
  29. Rahim, F.; Ullah, H.; Hussain, R.; Taha, M.; Khan, S.; Nawaz, M.; Nawaz, F.; Gilani, S.J.; Jumah, M.N.B. Thiadiazole based triazole/hydrazone derivatives: Synthesis, in vitro α-glucosidase inhibitory activity and in silico molecular docking study. J. Mol. Struct. 2023, 1287, 135619. [Google Scholar] [CrossRef]
  30. Riaz, N.; Iftikhar, M.; Saleem, M.; Rehman, A.U.; Ahmed, I.; Ashraf, M.; Shahnawaz; Rehman, J.; al-Rashida, M. A novel method for the synthesis of 1,2,4-triazole-derived heterocyclic compounds: Enzyme inhibition and molecular docking studies. J. Iran. Chem. Soc. 2020, 17, 1183–1200. [Google Scholar] [CrossRef]
  31. Le, T.D.; Nguyen, T.C.; Nuong Bui, T.M.; Dung Hoang, T.K.; Vu, Q.T.; Pham, C.T.; Dinh, C.P.; Jibril Abdullahi Alhaji, J.A.; Meervelt, L.V. Synthesis, structure and α-glucosidase inhibitor activity evaluation of some acetamide derivatives starting from 2-(naphthalen-1-yl) acetic acid, containing a 1,2,4-triazole. J. Mol. Struct. 2023, 1284, 135321. [Google Scholar] [CrossRef]
  32. Su, X.; Vicker, N.; Thomas, M.P.; Pradaux-Caggiano, F.; Halem, H.; Culler, M.D.; Potter, B.V.L. Discovery of Adamantyl Heterocyclic Ketones as Potent 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors. ChemMedChem. 2011, 6, 1439–1451. [Google Scholar] [CrossRef]
  33. Sharma, B.; Xie, L.; Yang, F.; Wang, W.; Zhou, Q.; Xiang, M.; Zhou, S.; Lv, W.; Jia, Y.; Pokhrel, L.; et al. Recent advance on PTP1B inhibitors and their biomedical applications. Eur. J. Med. Chem. 2020, 199, 112376. [Google Scholar] [CrossRef] [PubMed]
  34. Shahid, W.; Muhammad Ashraf, M.; Muhammad Saleem, M.; Bashir, B.; Muzaffar, S.; Ali, M.; Kaleem, A.; Rehman, A.U.; Amjad, H.; Bhattarai, K.; et al. Exploring phenylcarbamoylazinane-1,2,4-triazole thioethers as lipoxygenase inhibitors supported with in vitro, in silico and cytotoxic studies. Bioorg. Chem. 2021, 115, 105261. [Google Scholar] [CrossRef]
  35. Bivacqua, B.; Barreca, M.; Spano, V.; Raimondi, M.V.; Romeo, I.; Alcaro, S.; Graciela Andrei, G.; Barraja, P.; Montalbano, A. Insight into non-nucleoside triazole-based systems as viral polymerases inhibitors. Eur. J. Med. Chem. 2023, 249, 115136. [Google Scholar] [CrossRef]
  36. Abdellatif, K.R.A.; Abdelall, E.K.A.; Elshemy, H.A.H.; Philoppes, J.N.; Hassanein, E.H.M.; Kahk, N.M. Optimization of pyrazole-based compounds with 1,2,4-triazole-3-thiol moiety as selective COX-2 inhibitors cardioprotective drug candidates: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory, ulcerogenicity, cardiovascular evaluation, and molecular modeling studies. Bioorg. Chem. 2021, 114, 105122. [Google Scholar] [CrossRef]
  37. Mohassab, A.M.; Hassan, H.A.; Dalia Abdelhamid, D.; Mohamed Abdel-Aziz, M.; Dalby, K.N.; Kaoud, T.S. Novel quinoline incorporating 1,2,4-triazole/oxime hybrids: Synthesis, molecular docking, anti-inflammatory, COX inhibition, ulceroginicity and histopathological investigations. Bioorg. Chem. 2017, 75, 242–259. [Google Scholar] [CrossRef] [PubMed]
  38. Butt, A.R.S.; Abbasi, M.A.; Rehman, A.U.; Siddiqui, S.Z.; Hassan, M.; Raza, H.; Shah, S.A.A.; Seo, S.-Y. Synthesis and structure-activity relationship of elastase inhibiting novel ethylated thiazole-triazole acetamide hybrids: Mechanistic insights through kinetics and computational contemplations. Bioorg. Chem. 2019, 86, 197–209. [Google Scholar] [CrossRef] [PubMed]
  39. Bulut, N.; Kocyigit, U.M.; Gecibesler, I.H.; Dastan, T.; Karci, H.; Taslimi, P.; Dastan, D.S.; Gulcin, I.; Cetin, A. Synthesis of some novel pyridine compounds containing bis-1,2,4-triazole/thiosemicarbazide moiety and investigation of their antioxidant properties, carbonic anhydrase, and acetylcholinesterase enzymes inhibition profiles. J. Biochem. Mol. Toxicol. 2018, 32, e22006. [Google Scholar] [CrossRef]
  40. Mishra, D.; Fatima, A.; Kumar, P.; Munjal, N.S.; Singh, B.K.; Singh, R. Synthesis of Benzothiazole Linked Triazole Conjugates and Their Evaluation Against Cholinesterase Enzymes. ChemistrySelect 2022, 7, e20220360. [Google Scholar] [CrossRef]
  41. Siddiqui, S.Z.; Arfan, M.; Abbasi, M.A.; Rehman, A.U.; Shah, S.A.A.; Ashraf, M.; Hussain, S.; Saleem, R.S.Z.; Rafique, R.; Khan, K.M. Discovery of Dual Inhibitors of Acetyl and Butrylcholinesterase and Antiproliferative Activity of 1,2,4-Triazole-3-thiol: Synthesis and In Silico Molecular Study. ChemistrySelect 2020, 5, 6430–6439. [Google Scholar] [CrossRef]
  42. Aslan, E.K.; Sağlık, B.N.; Özkay, Y.; Palaska, E. Synthesis and Biological Evaluation of Benzoxazolone−Thiosemicarbazide, 1,2,4-Triazole, 1,3,4-Thiadiazole Derivatives as Cholinesterase Inhibitors. ChemistrySelect 2023, 8, e202302069. [Google Scholar] [CrossRef]
  43. Riaz, N.; Iftikhar, M.; Saleem, M.; Rehman, A.U.; Hussain, S.; Rehmat, F.; Afzal, Z.; Khawar, S.; Ashraf, M.; al-Rashida, M. New synthetic 1,2,4-triazole derivatives: Cholinesterase inhibition and molecular docking studies. Results Chem. 2020, 2, 100041. [Google Scholar] [CrossRef]
  44. Amjad, H.; Abbasi, M.A.; Siddiqui, S.Z.; Iqbal, J.; Rasool, S.; Ashraf, M.; Hussain, S.; Shah, S.A.A.; Imran, S.; Shahid, M.; et al. In vitro and in silico assessment of bioactivity properties and pharmacokinetic studies of new 3,5-disubstituted-1,2,4-triazoles. J. Mol. Struct. 2023, 1275, 134720. [Google Scholar] [CrossRef]
  45. Xu, M.; Peng, Y.; Zhu, L.; Wang, S.; Ji, J.; Rakesh, K.P. Triazole derivatives as inhibitors of Alzheimer’s disease: Current developments and structure-activity relationships. Eur. J. Med. Chem. 2019, 180, 656–672. [Google Scholar] [CrossRef]
  46. Edwards, L.; Isaac, M.; Johansson, M.; Kers, A.; Malmberg, J.; Mcleod, D.; Minidis, A.; Staaf, K.; Slassi, A.; Stefanac, T.; et al. Additional Heteropolycyclic Compounds and Their Use as Metabotropic Glutamate Receptor Antagonists. US Patent US 20070179188 A1, 2 August 2007. [Google Scholar]
  47. Svensson, M.; Tiden, A.-K.; Turek, D. Use of Derivatives of 2,4-Dihydro-[1,2,4]Triazole-3-Thione as Inhibitors of FTEH Enzyme Myeloperoxidase (MPO). International Patent WO 2004096781 A, 11 November 2004. [Google Scholar]
  48. Zohar, O.; Alkon, D.L. Therapeutic Effects of Bryostatins, Bryologs, and Other Related Substances on Head Trauma-Induced Memory Impairment and Traumatic Brain Injury. International Patent WO 2008143880 A2, 27 November 2008. [Google Scholar]
  49. Shi, L.; Zhang, X.Y.; Li Ping Cheng, L.P. Design, synthesis and biological evaluation of 1,3,4-triazole-3-acetamide derivatives as potent neuraminidase inhibitors. Bioorg. Med. Chem. Lett. 2022, 61, 128590. [Google Scholar] [CrossRef]
  50. El-Aleam, R.H.A.; George, R.F.; Lee, K.J.; Keeton, A.B.; Piazza, G.A.; Kamel, A.A.; El-Daly, M.E.; Hassan, G.S.; Abdel-Rahman, H.M. Design and synthesis of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as PDE 4B inhibitors endowed with bronchodilator activity. Arch. Pharm. 2019, 352, 1900002. [Google Scholar] [CrossRef] [PubMed]
  51. Huang, Y.-Y.; Yu, Y.-F.; Zhang, C.; Chen, Y.; Zhou, Q.; Li, Z.; Zhou, S.; Li, Z.; Guo, L.; Wu, D.; et al. Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors. J. Med. Chem. 2019, 62, 3707–3721. [Google Scholar] [CrossRef] [PubMed]
  52. Faridoon; Hussein, W.M.; Vella, P.; Islam, N.U.; Ollis, D.L.; Schenk, G.; McGeary, R.P. 3-Mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides as metallo-b-lactamase inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 380–386. [Google Scholar] [CrossRef]
  53. Sevaille, L.; Gavara, L.; Bebrone, C.; Luca, F.D.; Nauton, L.; Achard, M.; Mercuri, P.; Tanfoni, S.; Borgianni, L.; Guyon, C.; et al. 1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases. ChemMedChem 2017, 12, 972–985. [Google Scholar] [CrossRef]
  54. Gavara, L.; Verdirosa, F.; Sevaille, L.; Legru, A.; Corsica, G.; Nauton, L.; Mercuri, P.S.; Sannio, F.; De Luca, F.; Hadjadj, M.; et al. 1,2,4-Triazole-3-thione analogues with an arylakyl group at position 4 as metallo-β-lactamase inhibitors. Bioorg. Med. Chem. 2022, 72, 116964. [Google Scholar] [CrossRef]
  55. Hernandez, J.-F.; Gavara, L.; Docquier, J.-D.; Sevaille, L. Inhibitors of Metallo-Beta-Lactamases. European Patent EP 3653611 A1, 15 November 2018. [Google Scholar]
  56. Xiang, Y.; Chang, Y.-N.; Ge, Y.; Kang, J.S.; Zhang, Y.-L.; Liu, X.-L.; Oelschlaeger, P.; Yang, K.-W. Azolylthioacetamides as a potent scaffold for the development of metallo-β-lactamase inhibitors. Bioorg. Med. Chem. Lett. 2017, 27, 5225–5229. [Google Scholar] [CrossRef] [PubMed]
  57. Helgren, T.R.; Chen, C.; Wangtrakuldee, P.; Edwards, T.E.; Staker, B.L.; Abendroth, J.; Sankaran, B.; Housley, N.A.; Myler, P.J.; Audia, J.P.; et al. Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents. Bioorg. Med. Chem. 2017, 25, 813–824. [Google Scholar] [CrossRef]
  58. Menteşe, E.; Emirik, M.; Sökmen, B.B. Design, molecular docking and synthesis of novel 5,6-dichloro-2-methyl-1H-benzimidazole derivatives as potential urease enzyme inhibitors. Bioorg. Chem. 2019, 86, 151–158. [Google Scholar] [CrossRef]
  59. Ceylan, S.; Bektas, H.; Bayrak, H.; Demirbas, N.; Alpay-Karaoglu, S.; Ülker, S. Syntheses and Biological Activities of New Hybrid Molecules Containing Different Heterocyclic Moieties. Arch. Pharm. Chem. Life Sci. 2013, 346, 743–756. [Google Scholar] [CrossRef] [PubMed]
  60. Rezki, N.; Mayaba, M.M.; Al-blewi, F.F.; Aouad, M.R.; El Ashry, E.S.H. Click 1,4-regioselective synthesis, characterization, and antimicrobial screening of novel 1,2,3-triazoles tethering fluorinated 1,2,4-triazole and lipophilic side chain. Res. Chem. Intermed. 2017, 43, 995–1011. [Google Scholar] [CrossRef]
  61. Jain, R.K.; Mishra, V.K.; Kashaw, V. Synthesis and Antimicrobial Activity of Some New 1,2,4-Trizoles. Asian J. Chem. 2017, 29, 1317–1322. [Google Scholar] [CrossRef]
  62. Faiz, S.; Zahoor, A.F.; Ajmal, M.; Kamal, S.; Ahmad, S.; Abdelgawad, A.M.; Elnaggar, M.E. Design, Synthesis, Antimicrobial Evaluation, and Laccase Catalysis Effect of Novel Benzofuran–Oxadiazole and Benzofuran–Triazole Hybrids. J. Heterocycl. Chem. 2019, 56, 2839–2852. [Google Scholar] [CrossRef]
  63. Sonawane, A.D.; Rode, N.D.; Nawale, L.; Joshi, R.R.; Joshi, R.A.; Likhite, A.P.; Dhiman Sarkar, D. Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione as anti-mycobacterial agents. Chem. Biol. Drug Des. 2017, 90, 200–209. [Google Scholar] [CrossRef]
  64. Kini, S.G.; Bhat, A.; Pan, Z.; Dayan, F.E. Synthesis and antitubercular activity of heterocycle substituted diphenyl ether derivatives. J. Enzym. Inhib. Med. Chem. 2010, 25, 730–736. [Google Scholar] [CrossRef]
  65. Karczmarzyk, Z.; Swatko-Ossor, M.; Wysocki, W.; Drozd, M.; Ginalska, G.; Pachuta-Stec, A.; Pitucha, M. New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies. Molecules 2020, 25, 6033. [Google Scholar] [CrossRef]
  66. Koparir, M.; Orek, C.; Parlak, A.E.; Söylemez, A.; Koparir, P.; Karatepe, M.; Dastan, S.D. Synthesis and biological activities of some novel aminomethyl derivatives of 4-substituted-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones. Eur. J. Med. Chem. 2013, 63, 340–346. [Google Scholar] [CrossRef]
  67. Kokovina, T.S.; Gadomsky, S.Y.; Terentiev, A.A.; Sanina, N.A. A Novel Approach to the Synthesis of 1,3,4-Thiadiazole-2-amine Derivatives. Molecules 2021, 26, 5159. [Google Scholar] [CrossRef]
  68. Szécsényi, K.M.; Leovac, V.M.; Evans, I.R. Synthesis and characterisation of a novel polymeric Cd complex, catena-(l-thio)[bis(N-phenylthiourea] bis(dimethylsulphoxide)dichlorocadmium(II). J. Coord. Chem. 2006, 59, 523–530. [Google Scholar] [CrossRef]
  69. Tretyakov, B.A.; Gadomsky, S.Y.; Terentiev, A.A. A Reaction of N-Substituted Succinimides with Hydroxylamine as a Novel Approach to the Synthesis of Hydroxamic Acids. Organics 2023, 4, 186–195. [Google Scholar] [CrossRef]
  70. Rao, J.M.R.; Venkatesham, U.; Doppalapudi, S.R.; Kenchegowda, B.Y.; Fernand, G.; George, J.; Madhavan, G.R.; Naidu, G.P.; Kadambari, V.S.N.R.; Jagannath, S.; et al. Preparation of Azaadamantane Derivatives for Use as 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors. International Patent WO 201311115 0A1, 1 August 2013. [Google Scholar]
  71. Timokhin, B.V.; Golubin, A.I.; Vysotskaya, O.V.; Kron, V.A.; Oparina, L.A.; Gusarova, N.K.; Trofimov, B.A. Non-catalytic addition of 1,2,4-triazole to nucleophilic and electrophilic alkenes. Chem. Heterocycl. Compd. 2002, 38, 981–985. [Google Scholar] [CrossRef]
  72. Dixon, L.A. Polyphosphate Ester. In e-EROS Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2001. [Google Scholar] [CrossRef]
  73. Zhang, M.; Zou, B.; Gunaratna, M.J.; Weerasekara, S.; Tong, Z.; Nguyen, T.D.T.; Koldas, S.; Cao, W.S.; Pascual, C.; Xie, X.S.; et al. Synthesis of 1,3,4-oxadiazoles as selective T-tupe calcium channel inhibitors. Heterocycles 2020, 101, 145–164. [Google Scholar] [CrossRef] [PubMed]
  74. Samanta, S.; Lim, T.L.; Lam, Y. Synthesis and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold. ChemMedChem 2013, 8, 994–1001. [Google Scholar] [CrossRef] [PubMed]
  75. Damião, M.C.F.C.B.; Galaverna, R.; Kozikowski, A.P.; Eubanksc, J.; Pastre, J.C. Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles. React. Chem. Eng. 2017, 2, 896–907. [Google Scholar] [CrossRef]
  76. Peng, K.; Li, Y.; Bai, Y.; Jiang, T.; Sun, H.; Zhu, Q.; Xu, Y. Discovery of novel nonpeptide small-molecule NRP1 antagonists: Virtual screening, molecular simulation and structural modification. Bioorg. Med. Chem. 2020, 28, 115183. [Google Scholar] [CrossRef]
  77. Wang, Z.; Shi, H.; Shi, H. Novel synthesis of condensed heterocyclic systems containing 1,2,4-triazole ring. Synth. Commun. 2001, 31, 2841–2848. [Google Scholar] [CrossRef]
  78. Xiao, S.; Wang, X.; Xu, L.; Li, T.; Cao, J.; Zhao, Y. Novel panaxadiol triazole derivatives induce apoptosis in HepG-2 cells through the mitochondrial pathway. Bioorg. Chem. 2020, 102, 104078. [Google Scholar] [CrossRef]
  79. Shi, H.; Shi, H.; Wang, Z. Efficient one-pot synthesis of S-triazolo[3,4-b]-[1,3,5]thiadiazines containing a chiral side chain by double Mannich type reaction. J. Heterocycl. Chem. 2001, 38, 929–932. [Google Scholar] [CrossRef]
  80. Beyzaei, H.; Ghanbari, K.M.; Samareh, D.H.; Aryan, R. Synthesis, antimicrobial and antioxidant evaluation, and molecular docking study of 4,5-disubstituted 1,2,4-triazole-3-thiones. J. Mol. Struct. 2020, 1215, 128273. [Google Scholar] [CrossRef]
  81. Katkevica, S.; Salun, P.; Jirgensons, A. Synthesis of 5-substituted 3-mercapto-1,2,4-triazoles via Suzuki-Miyaura reaction. Tetrahedron Lett. 2013, 54, 4524–4525. [Google Scholar] [CrossRef]
  82. Taylor, R.W.; Romaine, I.M.; Liu, C.; Murthi, P.; Jones, P.L.; Waterson, A.G.; Sulikowski, G.A.; Zwiebel, L.J. Structure–Activity Relationship of a Broad-Spectrum Insect Odorant Receptor Agonist. ACS Chem. Biol. 2012, 7, 1647–1652. [Google Scholar] [CrossRef]
  83. Cheng, H.; Chen, C.; Cheng, J.; Song, W.; Sang, W.; Wang, Z. A Kind of Oxadiazole Heterocyclic Compound and Its Preparation Method and Application. People’s Republic of China Patent CN112300091A, 2 February 2021. [Google Scholar]
  84. Omar, Y.M.; Abdu-Allah, H.H.M.; Abdel-Moty, S.G. Synthesis, biological evaluation and docking study of 1,3,4-thiadiazolethiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX. Bioorg. Chem. 2018, 80, 461–471. [Google Scholar] [CrossRef] [PubMed]
  85. Wang, H.-Y.; Zhao, P.-S.; Li, R.-Q.; Zhou, S.-M. Synthesis, Crystal Structure and Quantum Chemical Study on 3-Phenylamino-4-Phenyl-1,2,4-Triazole-5-Thione. Molecules 2009, 14, 608–620. [Google Scholar] [CrossRef] [PubMed]
  86. Qian, C.; Xu, J.-M.; Wu, Q.; Lv, D.-S.; Lin, X.-F. Promiscuous acylase-catalyzed aza-Michael additions of aromatic N-heterocycles in organic solvent. Tetrahedron Lett. 2007, 48, 6100–6104. [Google Scholar] [CrossRef]
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Figure 1. Overview of the biological activities of 1,2,4-triazole-3-thiol derivatives (see Table 1 and Table 2 for specific molecular targets and activity against microbial strains).
Figure 1. Overview of the biological activities of 1,2,4-triazole-3-thiol derivatives (see Table 1 and Table 2 for specific molecular targets and activity against microbial strains).
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Figure 2. Literature-known approaches to the synthesis of 1,2,4-triazole-3-thiols.
Figure 2. Literature-known approaches to the synthesis of 1,2,4-triazole-3-thiols.
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Figure 3. Possible reaction pathways of thiosemicarbazide with carboxylic acids in the presence of PPE.
Figure 3. Possible reaction pathways of thiosemicarbazide with carboxylic acids in the presence of PPE.
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Scheme 1. Acylation of thiosemicarbazide derivatives with benzoic acid in the presence of PPE (R2 = H, Ethyl, Phenyl).
Scheme 1. Acylation of thiosemicarbazide derivatives with benzoic acid in the presence of PPE (R2 = H, Ethyl, Phenyl).
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Scheme 2. Synthetic scheme used in this work for the preparation of 1,2,4-triazole-3-thiol derivatives (R1 and R2 values are listed in Table 3).
Scheme 2. Synthetic scheme used in this work for the preparation of 1,2,4-triazole-3-thiol derivatives (R1 and R2 values are listed in Table 3).
Molecules 30 04422 sch002
Molecules 30 04422 g004
Figure 4. 1H NMR Spectral Comparison: 5-Phenyl-4H-1,2,4-triazole-3-thiol (top) and 5-Phenyl-1,3,4-thiadiazol-2-amine (bottom).
Figure 4. 1H NMR Spectral Comparison: 5-Phenyl-4H-1,2,4-triazole-3-thiol (top) and 5-Phenyl-1,3,4-thiadiazol-2-amine (bottom).
Molecules 30 04422 g004
Molecules 30 04422 g005
Figure 5. Structures of the reaction products isolated according to Scheme 2 instead of 2n and 2o, respectively.
Figure 5. Structures of the reaction products isolated according to Scheme 2 instead of 2n and 2o, respectively.
Molecules 30 04422 g005
Molecules 30 04422 sch003
Scheme 3. Attempted synthesis of 2n by reducing the amount of PPE, reaction time, and temperature.
Scheme 3. Attempted synthesis of 2n by reducing the amount of PPE, reaction time, and temperature.
Molecules 30 04422 sch003
Molecules 30 04422 sch004
Scheme 4. Synthesis of 2o via solvent replacement (chloroform with ethyl acetate).
Scheme 4. Synthesis of 2o via solvent replacement (chloroform with ethyl acetate).
Molecules 30 04422 sch004
Molecules 30 04422 sch005
Scheme 5. Comparative synthesis of 2p: developed method vs. hydrazide/ammonium thiocyanate route.
Scheme 5. Comparative synthesis of 2p: developed method vs. hydrazide/ammonium thiocyanate route.
Molecules 30 04422 sch005
Table 1. Therapeutic targets of 1,2,4-triazole-3-thiol derivatives.
Table 1. Therapeutic targets of 1,2,4-triazole-3-thiol derivatives.
Therapeutic AreasTargets
CancerATPase VCP/p97 [5]DHFR [13], FUT6 [14] PARP-1 [22,23]
BRD4 [6]HDACs [15,16]Tdp1 [24]
CA I, II, IV and IX [7,8,9,10]Hsp90 [17,18]TNKS1/2 [25]
CK1γ3 [11]KDM1A [19]PARP-5b [26]
DCN1-UBC12 int. [12]MMPs [7,20,21]TYMP [27]
Diabetesα-AMY [28], AGase [28,29,30,31]11b-HSD1 [32]PTP1B [33]
Inflammatory disordersALOX15 [34,35]COX1 [36,37]ELANE [38]
Neurological disordersAChE [30,39,40,41,42,43,44]AChRε [45]MPO [47]
BChE [30,40,41,42,43,44]mGlu5 [46]PKC [48]
Respiratory disordersNA [49], PDE4B [50]PDE10A [51]RNA pol. [35]
Bacterial infectionsMBLs [52,53,54,55,56]METAP1 [57]Urease [58]
Table 2. Antimicrobial activity of 1,2,4-triazole-3-thiol derivatives.
Table 2. Antimicrobial activity of 1,2,4-triazole-3-thiol derivatives.
Activity AgainstStrains
Gram-positive bacteriaA. oxydans [59]M. smegmatis [59]
B. cereus [59]M. tuberculosis [63,64,65]
B. subtilis [13,60,61,62]S. aureus. [13,59,60,61,62,66]
E. faecalis [59]S. pneumoniae [60]
Gram-negative bacteriaAcinetobacter sp. [59]P. aeruginosa [13,59,60,61]
E. coli [13,59,60,61,62,66]P. vulgaris [59]
K. oxytoca [59]S. marcescens [59]
K. pneumoniae [60,66]YPTB [59]
FungiA. flavus [66]M. anisopliae [62]
A. fumigatus [60,66]P. marneffei [66]
A. niger [61,62]S. cerevisiae [59]
C. albicans [13,59,60,61] T. harzianum [62]
C. tropicalis [59]T. mentagrophytes [66]
Table 3. Main results of the experimental implementation of Scheme 2.
Table 3. Main results of the experimental implementation of Scheme 2.
CompoundR1R2Yield, %
2aMolecules 30 04422 i001H30
2bEthyl27
2cPhenyl22
2dMolecules 30 04422 i002H34
2eMolecules 30 04422 i003H15
2fMolecules 30 04422 i004H34
2gMolecules 30 04422 i005H54
2hMolecules 30 04422 i006Ethyl20
2iMolecules 30 04422 i007H37
2jEthyl29
2kMolecules 30 04422 i008H35
2lEthyl13
2mPhenyl35
2nMolecules 30 04422 i009Phenyl-
2oMolecules 30 04422 i010H-
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Tretyakov, B.A.; Tikhonova, V.I.; Gadomsky, S.Y.; Sanina, N.A. Synthesis of 1,2,4-Triazole-3-Thiol Derivatives from Thiosemicarbazides and Carboxylic Acids Using Polyphosphate Ester. Molecules 2025, 30, 4422. https://doi.org/10.3390/molecules30224422

AMA Style

Tretyakov BA, Tikhonova VI, Gadomsky SY, Sanina NA. Synthesis of 1,2,4-Triazole-3-Thiol Derivatives from Thiosemicarbazides and Carboxylic Acids Using Polyphosphate Ester. Molecules. 2025; 30(22):4422. https://doi.org/10.3390/molecules30224422

Chicago/Turabian Style

Tretyakov, Bogdan A., Viktoria I. Tikhonova, Svyatoslav Y. Gadomsky, and Nataliya A. Sanina. 2025. "Synthesis of 1,2,4-Triazole-3-Thiol Derivatives from Thiosemicarbazides and Carboxylic Acids Using Polyphosphate Ester" Molecules 30, no. 22: 4422. https://doi.org/10.3390/molecules30224422

APA Style

Tretyakov, B. A., Tikhonova, V. I., Gadomsky, S. Y., & Sanina, N. A. (2025). Synthesis of 1,2,4-Triazole-3-Thiol Derivatives from Thiosemicarbazides and Carboxylic Acids Using Polyphosphate Ester. Molecules, 30(22), 4422. https://doi.org/10.3390/molecules30224422

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