Heterocyclizations based on N-(R-hydrazine-1-carbonothioyl)cycloalkancarboxamides: functionalized azoles and their antimicrobial activity
Keywords:N-(acylhydrazine-1-carbonothioyl)cycloalkanecarboxamides, heterocyclization, 1,3,4-thiadiazoles, 1,2,4-triazoles, antimicrobial activity
Synthesis and structural modification of azoles remains an important area of medical chemistry and allows to obtain new compounds with a wide range of biological activity. Among the significant number of azoles, 1,3,4-thiadiazoles and 1,2,4-triazoles attract special attention, among which are known drugs, larvicides, insecticides, growth regulators, etc. Even though heterocyclizations of functionally substituted hydrazines for their synthesis are well studied, N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides, and nowadays, remain reagents with undiscovered potential. Moreover, the introduction of lipophilic “pharmacophore” fragments (cycloalkanes) in the structure of 1,3,4-thiadiazoles and 1,2,4-triazoles is a promising direction for their modification. That should provide additional intermolecular interactions with enzymes and may lead to enhancement or alteration of the biological activity vector. Thus, the synthesis of new derivatives of this class of compounds and the study of their antibacterial properties remains an urgent problem of medical and organic chemistry.
Aim. To investigate the heterocyclization of N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxa-mides, to establish the structure and antibacterial activity of the synthesized compounds.
Materials and methods. Methods of organic synthesis, physical and physical-chemical methods of analysis of organic compounds (NMR 1H-spectroscopy, chromato-mass spectrometry, elemental analysis). The antimicrobial activity of the synthesized compounds was studied according to the generally accepted method for standard strains of microorganisms and fungi.
Results. The peculiarities of heterocyclization of N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides have been studied and the factors influencing this reaction have been elucidated. It was shown that these compounds under the conditions of the heterocyclization reaction in concentrated mineral acids form 5-R-2-amino-1,3,4-thiadiazoles. The intermediate undergoes additional hydrolysis by cleavage of the cycloalkanecarboxyl fragment. Alternative methods for the synthesis of 5-R-2-amino-1,3,4-thiadiazoles were proposed. For the first time, the original 4-cycloalkanecarbonyl-3-(amino-,phenyloxo-(thio)methyl-1,5-dihydro-4H-1,2,4-triazole-5-thiones were synthesized by prolonged heating of the corresponding disubstituted thiosemicarbazides. It was not possible to extend this reaction to other diacylthiosemicarbazides, the latter undergo heterocyclization in the presence of sodium hydroxide with the formation of the known 5-R-2,4-dihydro-3H-1,2,4-triazole-3-thiones. 1H NMR spectra were studied, analyzed, and regularities of splitting of characteristic protons in functionalized azoles were established. Conducted microbiological screening was showed that 5-R-2-amino-1,3,4-thiadiazoles, 4-cycloalkanecarbonyl-3-(amino-,phenyloxo-(thio)methyl-1,5-dihydro-4H-1,2,4-triazole-5-thiones and 5-R-2,4-dihydro-3H-1,2,4-triazole-3-thione were less effective antibacterial and antifungal agents (MIC 100–200 μg/ml) compared with N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides (MIC 3.125–200 μg/ml).
Conclusions. It was found that N-(R-hydrazine-1-carbonotioyl)cycloalkane-carboxamides, depending on the conditions of heterocyclization form 5-R-2-amino-1,3,4-thiadiazoles, 3-(phenyloxo-(thio)methyl-1,5-dihydro-4H-1,2,4-triazole-5-thiones or 5-R-2,4-dihydro-3H-1,2,4-triazole-3-thiones. It was established that synthesized azoles were shown less effective antimicrobial and antifungal activity in comparison with N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides.
Bedane, K. G., Singh, G. S. (2015). Reactivity and diverse synthetic applications of acyl isothiocyanates. ARKIVOC, 206-245. http://dx.doi.org/10.3998/ark.5550190.p009.052
Moharana, A. K., Dash, R. N., & Subudhi, B. B. (2020). Thiosemicarbazides: Updates on Antivirals Strategy. Mini reviews in medicinal chemistry, 20(20), 2135-2152. https://doi.org/10.2174/1389557520666200818212408
Metwally, M. A., Bondock, S., El-Azap, H., & Kandeel, E. E. M. (2011). Thiosemicarbazides: Synthesis and reactions. Journal of Sulfur Chemistry, 32(5), 489-519. https://doi.org/10.1080/17415993.2011.601869
Vincent-Rocan, J. F., & Beauchemin, A. M. (2016). N-Isocyanates, N-Isothiocyanates and Their Masked/Blocked Derivatives: Synthesis and Reactivity. Synthesis, 48(21), 3625-3645. https://doi.org/10.1055/s-0036-1588066
Nora De Souza, M. V. (2005). Synthesis and biological activity of natural thiazoles: An important class of heterocyclic compounds. Journal of Sulfur Chemistry, 26(4-5), 429-449. https://doi.org/10.1080/17415990500322792
Jain A. K., Sharma S., Vaidya A., Ravichandran V., & Agrawal, R. K. (2013). 1,3,4-Thiadiazole and its Derivatives: A Review on Recent Progress in Biological Activities. Chemical Biology & Drug Design, 81(5), 557-576. https://doi.org/10.1111/cbdd.12125
Hu Y., Li C.-Y., Wang X.-M., Yang Y.-H., Zhu H.-L. (2014). 1,3,4-Thiadiazole: Synthesis, Reactions, and Applications in Medicinal Agricultural and Materials Chemistry. Chemical Reviews, 114(10), 5572-5610. https://doi.org/10.1021/cr400131u
Sukinah, H. A., & Abdelwahed, R. S. (2020). Review of the synthesis and biological activity of thiazoles, Synthetic Communications, 51(5), 670-700. https://doi.org/10.1080/00397911.2020.1854787
Sahiba, N., Sethiya, A., Soni, J., Agarwal, D. K., & Agarwal, S. (2020). Saturated Five-Membered Thiazolidines and Their Derivatives: From Synthesis to Biological Applications. Topics in Current Chemistry, 378, 34. https://doi.org/10.1007/s41061-020-0298-4
Sathish Kumar, S., & P. Kavitha, H. (2013). Synthesis and Biological Applications of Triazole Derivatives – A Review. Mini-Reviews in Organic Chemistry, 10(1), 40-65. https://doi.org/10.2174/1570193x11310010004
Maddila, S., Pagadala, R., & Jonnalagadda, S. (2013). 1,2,4-Triazoles: A Review of Synthetic Approaches and the Biological Activity. Letters in Organic Chemistry, 10(10), 693-714. https://doi.org/10.2174/157017861010131126115448
Gümüş, M., Yakan, M., & Koca, İ. (2019). Recent advances of thiazole hybrids in biological applications. Future Medicinal Chemistry, 11(15), 1979-1998. https://doi.org/10.4155/fmc-2018-0196.
Matysiak, J. (2015). Biological and pharmacological activities of 1,3,4-thiadiazole based compounds. Mini reviews in medicinal chemistry, 15(9), 762-775. https://doi.org/10.2174/1389557515666150519104057
Sahu, J. K., Ganguly, S., & Kaushik, A. (2013). Triazoles: a valuable insight into recent developments and biological activities. Chinese journal of natural medicines, 11(5), 456-465. https://doi.org/10.1016/S1875-5364(13)60084-9
DrugBank Online : [database]. https://go.drugbank.com/drugs
Antypenko, L., Meyer, F., Kholodniak, O., Sadykova, Z., Jirásková, T., Troianova, A., Buhaiova, V., Cao, S., Kovalenko, S., Garbe, L. A., & Steffens, K. G. (2019). Novel acyl thiourea derivatives: Synthesis, antifungal activity, gene toxicity, drug-like and molecular docking screening. Archiv der Pharmazie, 352(2), e1800275. https://doi.org/10.1002/ardp.201800275
Kholodniak, O. V., Sokolova, K. V., Kovalenko, S. I., & Pidpletnya, O. A. (2020). Directed search for compounds that affect the excretory function of rat kidneys, among new cycloalkylcarbonyl thioureas and thiosemicarbazides derivatives. Medychna ta klinichna khimiia - Medical and Clinical Chemistry, (2), 5-16. https://doi.org/10.11603/mcch.2410-681X.2020.v.i2.11351
Kholodniak, O. V., Stavytskyi, V. V., Kazunin, M. S., Bukhtiayrova, N. V., Berest, G. G., Belenichev, I. F., & Kovalenko, S. I. (2021). Design, synthesis and anticonvulsant activity of new Diacylthiosemicarbazides. Biopolymers and Cell, 37(2), 125-142. https://doi.org/10.7124/bc.000A46
Clinical and Laboratory Standards Institute. (2006). Performance standards for antimicrobial disk susceptibility tests, (9th ed) CLSI standard M2-A9. Wayne, PA: Clinical and Laboratory Standards Institute.
Barbosa, G. A. D., & de Aguiar, A. P. (2019). Synthesis of 1,3,4-Thiadiazole Derivatives and Microbiological Activities: A Review. Revista Virtual de Química, 11(3), 806-848. https://doi.org/10.21577/1984-6835.20190058
Baranac-Stojanović, M., & Stojanović, M. (2013). 1H NMR chemical shifts of cyclopropane and cyclobutane: a theoretical study. The Journal of organic chemistry, 78(4), 1504-1507. https://doi.org/10.1021/jo3025863
Breitmaier E. (2002). Structure elucidation by NMR in organic chemistry: a practical guide (3rd ed). Wiley. https://doi.org/10.1002/0470853069
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