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Research Article | DOI: https://doi.org/10.31579/2688-7517/162
1 National Military Medical Clinical Center "Main Military Clinical Hospital", Ukraine.
2 Ukrainian Military Medical Academy, Ukraine.
3 Zaporizhzhia State Medical and Pharmaceutical University, Ukraine.
*Corresponding Author: Bushuyeva І. V. Zaporizhzhia State Medical and Pharmaceutical University, Ukraine.
Citation: : Prytula R.L, Shmatenko O.P, Bushuyeva І. V, Parchenko V.V, (2024), Some Aspects of Getting and Conversion Among the New 3-Thio- and 3-Thio-4-Amino Derivatives of 1,2,4-Triazole (Literature Review). J. Pharmaceutics and Pharmacology Research, 7(2); DOI:10.31579/2688-7517/162
Copyright: © 2024, Bushuyeva І. V. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 02 December 2023 | Accepted: 02 January 2024 | Published: 01 February 2024
Keywords: 3-thio- and 3-thio-4-amino derivatives of 1,2,4-triazole; physicochemical properties; synthesis; chemical modification
For a long time, synthetic drugs have been widely used for the prevention and treatment of various diseases. Derivatives of 1,2,4-triazole are structural fragments of compounds that make up a significant proportion of the substances of well-known effective drugs. 1,2,4-Triazole is a kind of "framework" for the new molecules’ getting. Publications of domestic and foreign authors convincingly prove the prospect of finding new substances in a number of substituted 1,2,4-triazoles [1-3]. Among new optical materials and photosensitizers, 1,2,4-triazole derivatives account for a significant share. They are also used in the practice of manufacturing various dyes, antioxidants, fuel and lubricant additives, some of them have found a use as corrosion inhibitors,etc
For a long time, synthetic drugs have been widely used for the prevention and treatment of various diseases. Derivatives of 1,2,4-triazole are structural fragments of compounds that make up a significant proportion of the substances of well-known effective drugs. 1,2,4-Triazole is a kind of "framework" for the new molecules’ getting. Publications of domestic and foreign authors convincingly prove the prospect of finding new substances in a number of substituted 1,2,4-triazoles [1-3]. Among new optical materials and photosensitizers, 1,2,4-triazole derivatives account for a significant share. They are also used in the practice of manufacturing various dyes, antioxidants, fuel and lubricant additives, some of them have found a use as corrosion inhibitors, etc. Most often, they are a perspective for the creation of new original medicines for both humane medicine and veterinary practice. The continuous searching process of new promising molecules among 1,2,4-triazole derivatives, which includes stages starting from the initial compounds’ synthesis and certain transformations and ending with the study of biological properties, inspires scientists to continue research in this direction. It should be noted that despite the sufficient amount of information on the synthesis and transformations of a number of 1,2,4-triazole derivatives, some synthetic issues of new 3-thio- and 3-thio-4-amino derivatives of the 1,2,4-triazole are not sufficiently explained.
of our work was to summarize the available literary sources, the material which relates to the synthesis methods, studies of the physicochemical properties of 3-thio- and 3-thio-4-amino derivatives of the 1,2,4-triazole.
To achieve the goal, theoretical methods were used: bibliographic, information search, review, generalization. The scientific material was the results of fundamental and applied research by domestic and foreign specialists, namely: leading scientists’ articles, thesis studies, analytical reports and reviews on the above-mentioned issue.
A well-known classic method for the synthesis of 3-thioderivatives of 1,2,4-triazole is the method described in the monograph [4-7]. Other sources convincingly prove that various alkyl-, aryl-, heterylcarboxylic acids can be used as starting compounds for the synthesis of 3-S-derivatives of 1,2,4-triazoles [4, 6] [ 8-10]. In future, 2-acylhydrazinocarbothioamides are obtained from hydrazides [11]. The presented methods of synthesis are united by a common stage of cyclization of the corresponding 2-acylhydrazinocarbothioamides in an alkaline medium (Figure. 1).
R=Alk, Ar, Het, R1=Alk, R2=Ar (Ph)
Figure 1: Synthesis scheme of S-derivatives of the 1,2,4-triazole
The arylisothiocyanates use in the synthesis of the 1,2,4-triazole derivatives has been devoted to a large number of works [12-15], but the simple method described in the work [5] deserves the most attention. The corresponding aryl isothiocyanates are synthesized through the intermediate stage of obtaining the corresponding arylammonium dithiocarbamates using aniline, 2-methylaniline, 2-methoxyaniline, or 4-bromoaniline as starting amines (Fig. 2).
R1= Н, 2- methyl, 2- methoxy, 4-bromine
Figure 2: Obtaining scheme of arylisothiocyanates’ number
It has been proven that combinations of various typical pharmacophores in the form of five- and six-membered heterocycles’ fragments and the 1,2,4-triazole can lead to the appearance of a structure with high biological activity [16-19]. The introduction of the thiophene fragment
and various alkyl or aryl derivatives in the 4-position of the 1,2,4-triazole ring leads to the appearance of molecules with high activity indicators [20]. The thus obtained 4-R-3-(thiophen-2-ylmethyl)-1H-1,2,4-triazole-5(4H)-thion has antifungal activity (Figure. 3).
R=C2H5, C6H5, CH2-C6H5, 4-CH3-C6H4, 4-BrC6H4, 4-ClC6H4
Figurea 3: Synthesis scheme of 4-R-3-(thiophen-2-ylmethyl)-1H-1,2,4-triazole-5(4H)-thions
The synthesis of 5-(4-methyl-(phenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)-pyrolidin-2-ones by a team of French scientists proves the prospects of new substituted 1,2,4-triazole [21]. 1-R-5-oxo-pyrrolidine-2-carbohydrazide was used as the starting compound (Figure. 4).
R=H, C6H5CH2, R1 = H3C, C6H5
Figure 4: Synthesis scheme of 5-(4-R1-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyrrolidin-2-ones
The combination of 1,2,4-triazole-3-thione and pyrazole derivatives resulted in compounds with potential anti-inflammatory, analgesic, and antipyretic activity [20-22]. Scientists have synthesized 4-R-3-(4-R1-1-aryl-1H-pyrazole-3-yl)-1H-1,2,4-triazole-5(4H)-thions in high yields (Figure. 5) .
R=H, C6H5CH2, R1 = H3C, C6H5
Figure 5: Synthesis scheme of 4-R-3-(4-R1-1-phenyl-1H-pyrazole-3-yl)-1H-1,2,4-triazole-5(4H)-thions
Another group of scientists has managed to combine 1,2,4-triazole-3-thion and imidazole, obtaining compounds with antiparasitic action [23-24]. The authors have also succeeded in synthesizing molecules with oxazole and 1,2,4-triazole residues, which possess psychostimulant activity (Figure. 6).
R = CH3, C4H9, C6H5, 4-CH3C6H4, 4-FC6H4, 4-ClC6H4,
4-BrC6H4, 4-O2NC6H44-OCH3, naphthyl
Figure 6. Synthesis scheme of 1,2,4-triazole and oxazole derivatives
The condensed derivatives’ synthesis of 1,2,4-triazole is gaining popularity [20]. Thus, for biological research, a number of 5-((1H-benzo-1,2,3-triazole-1-yl)methyl)-4-R-4H-1,2,4-triazole-3-thiols and 3- (1-benzyl-1H-indol-3-yl)-4-phenyl-1H-1,2,4-triazole-5(4H)-thion (Figure. 7).
R = C6H5, 2-, 3- та 4-CH3C6H5
Figure 7: Synthesis scheme of 5-((1H-benzo-1,2,3-triazole-1-yl)methyl)-4-R-4H-1,2,4-triazole-3-thiols and 3-(1-benzyl-1H-indol-3-yl)-4-phenyl-1H-1,2,4-triazole-5(4H)-thion
In some works, there are alternative, simple and effective obtaining methods of 2-acylhydrazinocarbothioamides by the interaction of thiosemicarbazide with anhydrides or haloanhydrides of carboxylic acids [25-27]. Closure of the 1,2,4-triazole cycle takes place as in the previous cases in an alkaline medium (Figure. 8).
R=Alk, Ar, Het
Figure 8: Synthesis of 5-R-1,2,4-triazole-3-thiols
Another group of authors has proved the closure of the 1,2,4-triazole cycle by catalytic amounts of Cu2+ salts [28]. Similar processes are caused by the fact that 2-R-hydrazinocarbothioamides contain a fragment of an
unsaturated hydrocarbon and an increase in temperature in the presence of sodium or potassium hydroxide excess can lead to the unsaturated bonds’ breaking (Figure. 9).
Figure 9: Synthesis of 2-(4-allyl-5-thio-1,2,4-triazole-3-yl)phenol
In the articles, scientists also present a synthesis scheme of the 5-heteryl-substituted 1,2,4-triazole-3-thion by the interaction of esters of heterylcarboxylic acids with thiosemicarbazide in the presence of sodium methanolate [29-30]. The corresponding thiols were isolated by adding the 5-R-1,2,4-triazole-3-thiolate acids to sodium (Figure. 10).
R=Het
Figure 10: Synthesis scheme of 5-substituted 2,4-dihydro-1,2,4-triazole-3-thiols
Polish scientists have described in details the synthesis of the 1,2,4-triazole-3-thions by the interaction of 2-acylhydrazinocarbodithioates with aliphatic amines [31]. At the same time, 3,4-disubstituted 1,2,4-triazole-3-thions are formed in one stage (Figure. 11).
R = R’ = Alk, Ar
Figure 11: Synthesis of 5,4-disubstituted 1,2,4-triazole-3-thions
Cyclocondensation of the 1,2,4-triazole-3-thions and R-(aminomethylthiomethyl)-2-benzylidene hydrazides in the presence of ferrum (III) chloride in concentrated acetic acid takes place at a temperature of 90°C with short heating (Figure. 12).
R = R’ = Ar
Figure 12: Cyclocondensation of R-(aminomethylthiomethyl)-2-benzylidene hydrazides
3-Thioderivatives of 1,2,4-triazoles can also be synthesized by thionation of 1 or 4 substituted 1,2,4-triazoles [32-34]. There is also a well-known method of thionation of 1-R-1,2,4-triazole-3-ones under stricter conditions - by heating the starting substances in dimethylformamide for 16 hours at a temperature of 150°C (Figure. 13).
R = R1=Alk
Figure 13. Thionation of substituted 1,2,4-triazole
The original obtaining method of 5,5'-alkylenebis(4H-1,2,4-triazole-3-thions) is proposed by scientists in works [35-36]. It was established that this process can be carried out by two methods (Figure. 14). According to the first method, dicarboxylic acids are used as starting compounds, the
second method provides for obtaining esters, hydrazides of alkylenedicarboxylic acids, which, under the action of potassium (or ammonium) thiocyanates in a hydrochloric acid environment, are transformed into alkylbis(hydrazinocarbothioamides).
Figure 14: Synthesis scheme of 5,5'-alkylenebis(4H-1,2,4-triazole-3-thions)A well-known classic method for the synthesis of 3-thioderivatives of 1,2,4-triazole is the method described in the monograph [4-7]. Other sources convincingly prove that various alkyl-, aryl-, heterylcarboxylic acids can be used as starting compounds for the synthesis of 3-S-derivatives of 1,2,4-triazoles [4, 6] [ 8-10]. In future, 2-acylhydrazinocarbothioamides are obtained from hydrazides [11]. The presented methods of synthesis are united by a common stage of cyclization of the corresponding 2-acylhydrazinocarbothioamides in an alkaline medium (Figure. 1).
R=Alk, Ar, Het, R1=Alk, R2=Ar (Ph)
Figure 1: Synthesis scheme of S-derivatives of the 1,2,4-triazole
The arylisothiocyanates use in the synthesis of the 1,2,4-triazole derivatives has been devoted to a large number of works [12-15], but the simple method described in the work [5] deserves the most attention. The corresponding aryl isothiocyanates are synthesized through the intermediate stage of obtaining the corresponding arylammonium dithiocarbamates using aniline, 2-methylaniline, 2-methoxyaniline, or 4-bromoaniline as starting amines (Fig. 2).
R1= Н, 2- methyl, 2- methoxy, 4-bromine
Figure 2: Obtaining scheme of arylisothiocyanates’ number
It has been proven that combinations of various typical pharmacophores in the form of five- and six-membered heterocycles’ fragments and the 1,2,4-triazole can lead to the appearance of a structure with high biological activity [16-19]. The introduction of the thiophene fragment
and various alkyl or aryl derivatives in the 4-position of the 1,2,4-triazole ring leads to the appearance of molecules with high activity indicators [20]. The thus obtained 4-R-3-(thiophen-2-ylmethyl)-1H-1,2,4-triazole-5(4H)-thion has antifungal activity (Figure. 3).
R=C2H5, C6H5, CH2-C6H5, 4-CH3-C6H4, 4-BrC6H4, 4-ClC6H4
Figurea 3: Synthesis scheme of 4-R-3-(thiophen-2-ylmethyl)-1H-1,2,4-triazole-5(4H)-thions
The synthesis of 5-(4-methyl-(phenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)-pyrolidin-2-ones by a team of French scientists proves the prospects of new substituted 1,2,4-triazole [21]. 1-R-5-oxo-pyrrolidine-2-carbohydrazide was used as the starting compound (Figure. 4).
R=H, C6H5CH2, R1 = H3C, C6H5
Figure 4: Synthesis scheme of 5-(4-R1-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyrrolidin-2-ones
The combination of 1,2,4-triazole-3-thione and pyrazole derivatives resulted in compounds with potential anti-inflammatory, analgesic, and antipyretic activity [20-22]. Scientists have synthesized 4-R-3-(4-R1-1-aryl-1H-pyrazole-3-yl)-1H-1,2,4-triazole-5(4H)-thions in high yields (Figure. 5) .
R=H, C6H5CH2, R1 = H3C, C6H5
Figure 5: Synthesis scheme of 4-R-3-(4-R1-1-phenyl-1H-pyrazole-3-yl)-1H-1,2,4-triazole-5(4H)-thions
Another group of scientists has managed to combine 1,2,4-triazole-3-thion and imidazole, obtaining compounds with antiparasitic action [23-24]. The authors have also succeeded in synthesizing molecules with oxazole and 1,2,4-triazole residues, which possess psychostimulant activity (Figure. 6).
R = CH3, C4H9, C6H5, 4-CH3C6H4, 4-FC6H4, 4-ClC6H4,
4-BrC6H4, 4-O2NC6H44-OCH3, naphthyl
Figure 6. Synthesis scheme of 1,2,4-triazole and oxazole derivatives
The condensed derivatives’ synthesis of 1,2,4-triazole is gaining popularity [20]. Thus, for biological research, a number of 5-((1H-benzo-1,2,3-triazole-1-yl)methyl)-4-R-4H-1,2,4-triazole-3-thiols and 3- (1-benzyl-1H-indol-3-yl)-4-phenyl-1H-1,2,4-triazole-5(4H)-thion (Figure. 7).
R = C6H5, 2-, 3- та 4-CH3C6H5
Figure 7: Synthesis scheme of 5-((1H-benzo-1,2,3-triazole-1-yl)methyl)-4-R-4H-1,2,4-triazole-3-thiols and 3-(1-benzyl-1H-indol-3-yl)-4-phenyl-1H-1,2,4-triazole-5(4H)-thion
In some works, there are alternative, simple and effective obtaining methods of 2-acylhydrazinocarbothioamides by the interaction of thiosemicarbazide with anhydrides or haloanhydrides of carboxylic acids [25-27]. Closure of the 1,2,4-triazole cycle takes place as in the previous cases in an alkaline medium (Figure. 8).
R=Alk, Ar, Het
Figure 8: Synthesis of 5-R-1,2,4-triazole-3-thiols
Another group of authors has proved the closure of the 1,2,4-triazole cycle by catalytic amounts of Cu2+ salts [28]. Similar processes are caused by the fact that 2-R-hydrazinocarbothioamides contain a fragment of an
unsaturated hydrocarbon and an increase in temperature in the presence of sodium or potassium hydroxide excess can lead to the unsaturated bonds’ breaking (Figure. 9).
Figure 9: Synthesis of 2-(4-allyl-5-thio-1,2,4-triazole-3-yl)phenol
In the articles, scientists also present a synthesis scheme of the 5-heteryl-substituted 1,2,4-triazole-3-thion by the interaction of esters of heterylcarboxylic acids with thiosemicarbazide in the presence of sodium methanolate [29-30]. The corresponding thiols were isolated by adding the 5-R-1,2,4-triazole-3-thiolate acids to sodium (Figure. 10).
R=Het
Figure 10: Synthesis scheme of 5-substituted 2,4-dihydro-1,2,4-triazole-3-thiols
Polish scientists have described in details the synthesis of the 1,2,4-triazole-3-thions by the interaction of 2-acylhydrazinocarbodithioates with aliphatic amines [31]. At the same time, 3,4-disubstituted 1,2,4-triazole-3-thions are formed in one stage (Figure. 11).
R = R’ = Alk, Ar
Figure 11: Synthesis of 5,4-disubstituted 1,2,4-triazole-3-thions
Cyclocondensation of the 1,2,4-triazole-3-thions and R-(aminomethylthiomethyl)-2-benzylidene hydrazides in the presence of ferrum (III) chloride in concentrated acetic acid takes place at a temperature of 90°C with short heating (Figure. 12).
R = R’ = Ar
Figure 12: Cyclocondensation of R-(aminomethylthiomethyl)-2-benzylidene hydrazides
3-Thioderivatives of 1,2,4-triazoles can also be synthesized by thionation of 1 or 4 substituted 1,2,4-triazoles [32-34]. There is also a well-known method of thionation of 1-R-1,2,4-triazole-3-ones under stricter conditions - by heating the starting substances in dimethylformamide for 16 hours at a temperature of 150°C (Figure. 13).
R = R1=Alk
Figure 13. Thionation of substituted 1,2,4-triazole
The original obtaining method of 5,5'-alkylenebis(4H-1,2,4-triazole-3-thions) is proposed by scientists in works [35-36]. It was established that this process can be carried out by two methods (Figure. 14). According to the first method, dicarboxylic acids are used as starting compounds, the
second method provides for obtaining esters, hydrazides of alkylenedicarboxylic acids, which, under the action of potassium (or ammonium) thiocyanates in a hydrochloric acid environment, are transformed into alkylbis(hydrazinocarbothioamides).
Figure 14: Synthesis scheme of 5,5'-alkylenebis(4H-1,2,4-triazole-3-thions)
The analysis of literary sources shows the prospect of finding new biologically active molecules among the 1,2,4-triazole derivatives. According to the results of the research, a generalization of publicly available literary material on synthesis methods, research of physicochemical properties of the 3-thio- and 3-thio-4-amino derivatives of the 1,2,4-triazole was carried out. A number of new compounds, which are formed during the transformation of the specified derivatives’ series, have been studied in detail. The analysis of literary sources has revealed
simple and promising methods of obtaining and converting the 3-thio- and 3-thio-4-amino derivatives of the 1,2,4-triazole.
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