Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity
Background: In the era of resistance, the design and search for new “small” molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of medicinal chemistry. In this regard, we...
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MDPI AG
2025-01-01
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| author | Kostiantyn Shabelnyk Alina Fominichenko Oleksii Antypenko Olexandr Gaponov Svitlana Koptieva Svitlana Shyshkina Oleksii Voskoboinik Sergiy Okovytyy Serhii Kovalenko Valentyn Oksenych Oleksandr Kamyshnyi |
| author_facet | Kostiantyn Shabelnyk Alina Fominichenko Oleksii Antypenko Olexandr Gaponov Svitlana Koptieva Svitlana Shyshkina Oleksii Voskoboinik Sergiy Okovytyy Serhii Kovalenko Valentyn Oksenych Oleksandr Kamyshnyi |
| author_sort | Kostiantyn Shabelnyk |
| collection | DOAJ |
| description | Background: In the era of resistance, the design and search for new “small” molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of medicinal chemistry. In this regard, we developed and successfully implemented a strategy for the search for new hybrid molecules, namely, the not broadly known [2-(3-R-1<i>H</i>-[1,2,4]-triazol-5-yl)phenyl]amines. They can act as “building blocks” and allow for the introduction of certain structural motifs into the desired final products in order to enhance the antistaphylococcal effect. Methods: The “one-pot” synthesis of the latter is based on the conversion of substituted 4-hydrazinoquinazolines or substituted 2-aminobenzonitriles and carboxylic acid derivatives to the target products. The possible molecular mechanism of the synthesized compounds (DNA gyrase inhibitors) was investigated and discussed using molecular docking, and their further study for antistaphylococcal activity was substantiated. Results: A significant part of the obtained compounds showed high antibacterial activity against <i>Staphylococcus aureus</i> (MIC: 10.1–62.4 µM) and 5-bromo-2-(3-(furan-3-yl)-1<i>H</i>-1,2,4-triazol-5-yl)aniline and 5-fluoro-2-(3-(thiophen-3-yl)-1<i>H</i>-1,2,4-triazol-5-yl)aniline, with MICs of 5.2 and 6.1 µM, respectively, approaching the strength of the effect of the reference drug, “Ciprofloxacin” (MIC: 4.7 µM). The conducted SAR and ADME analyses confirm the prospects of the further structural modification of these compounds. The obtained [2-(3-R-1<i>H</i>-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antimicrobial activity and deserve further structural modification and detailed study as effective antistaphylococcal agents. The SAR analysis revealed that the presence of a cycloalkyl or electron-rich heterocyclic fragment in the third position of the triazole ring was essential for the antibacterial activity of the obtained compounds. At the same time, the introduction of a methyl group into the aniline moiety led to an enhancement of activity. The introduction of halogen into the aniline fragment has an ambiguous effect on the level of antistaphylococcal activity and depends on the nature of the substituent in the third position. Conclusions: Obtained [2-(3-R-1<i>H</i>-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antistaphylococcal activity and deserve for further detailed study as effective antibacterial agents. |
| format | Article |
| id | doaj-art-d4a0332c62434c02be3d1d08f7c79181 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-d4a0332c62434c02be3d1d08f7c791812025-01-24T13:45:19ZengMDPI AGPharmaceuticals1424-82472025-01-011818310.3390/ph18010083Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and ActivityKostiantyn Shabelnyk0Alina Fominichenko1Oleksii Antypenko2Olexandr Gaponov3Svitlana Koptieva4Svitlana Shyshkina5Oleksii Voskoboinik6Sergiy Okovytyy7Serhii Kovalenko8Valentyn Oksenych9Oleksandr Kamyshnyi10Department of Pharmaceutical, Organic and Bioorganic chemistry, Zaporizhzhia State Medical and Pharmaceutical University, 69000 Zaporizhzhia, UkraineBacteriological Laboratory, Zaporizhzhia Regional Hospital, 69600 Zaporizhzhia, UkraineDepartment of Pharmaceutical, Organic and Bioorganic chemistry, Zaporizhzhia State Medical and Pharmaceutical University, 69000 Zaporizhzhia, UkraineInstitute of Chemistry and Geology, Oles Honchar Dnipro National University, 49000 Dnipro, UkraineInstitute of Chemistry and Geology, Oles Honchar Dnipro National University, 49000 Dnipro, UkraineSSI “Institute for Single Crystals” of the National Academy of Sciences of Ukraine, 61072 Kharkiv, UkraineDepartment of Composite Materials, Chemistry and Technologies, National University «Zaporizhzhia Polytechnic», 69063 Zaporizhzhia, UkraineInstitute of Chemistry and Geology, Oles Honchar Dnipro National University, 49000 Dnipro, UkraineInstitute of Chemistry and Geology, Oles Honchar Dnipro National University, 49000 Dnipro, UkraineFaculty of Medicine, University of Bergen, 5020 Bergen, NorwayDepartment of Microbiology, Virology and Immunology, I. Horbachevsky Ternopil State Medical University, 46001 Ternopil, UkraineBackground: In the era of resistance, the design and search for new “small” molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of medicinal chemistry. In this regard, we developed and successfully implemented a strategy for the search for new hybrid molecules, namely, the not broadly known [2-(3-R-1<i>H</i>-[1,2,4]-triazol-5-yl)phenyl]amines. They can act as “building blocks” and allow for the introduction of certain structural motifs into the desired final products in order to enhance the antistaphylococcal effect. Methods: The “one-pot” synthesis of the latter is based on the conversion of substituted 4-hydrazinoquinazolines or substituted 2-aminobenzonitriles and carboxylic acid derivatives to the target products. The possible molecular mechanism of the synthesized compounds (DNA gyrase inhibitors) was investigated and discussed using molecular docking, and their further study for antistaphylococcal activity was substantiated. Results: A significant part of the obtained compounds showed high antibacterial activity against <i>Staphylococcus aureus</i> (MIC: 10.1–62.4 µM) and 5-bromo-2-(3-(furan-3-yl)-1<i>H</i>-1,2,4-triazol-5-yl)aniline and 5-fluoro-2-(3-(thiophen-3-yl)-1<i>H</i>-1,2,4-triazol-5-yl)aniline, with MICs of 5.2 and 6.1 µM, respectively, approaching the strength of the effect of the reference drug, “Ciprofloxacin” (MIC: 4.7 µM). The conducted SAR and ADME analyses confirm the prospects of the further structural modification of these compounds. The obtained [2-(3-R-1<i>H</i>-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antimicrobial activity and deserve further structural modification and detailed study as effective antistaphylococcal agents. The SAR analysis revealed that the presence of a cycloalkyl or electron-rich heterocyclic fragment in the third position of the triazole ring was essential for the antibacterial activity of the obtained compounds. At the same time, the introduction of a methyl group into the aniline moiety led to an enhancement of activity. The introduction of halogen into the aniline fragment has an ambiguous effect on the level of antistaphylococcal activity and depends on the nature of the substituent in the third position. Conclusions: Obtained [2-(3-R-1<i>H</i>-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antistaphylococcal activity and deserve for further detailed study as effective antibacterial agents.https://www.mdpi.com/1424-8247/18/1/83triazole«one-pot» synthesismolecular dockingantistaphylococcal activity |
| spellingShingle | Kostiantyn Shabelnyk Alina Fominichenko Oleksii Antypenko Olexandr Gaponov Svitlana Koptieva Svitlana Shyshkina Oleksii Voskoboinik Sergiy Okovytyy Serhii Kovalenko Valentyn Oksenych Oleksandr Kamyshnyi Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity Pharmaceuticals triazole «one-pot» synthesis molecular docking antistaphylococcal activity |
| title | Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity |
| title_full | Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity |
| title_fullStr | Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity |
| title_full_unstemmed | Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity |
| title_short | Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity |
| title_sort | antistaphylococcal triazole based molecular hybrids design synthesis and activity |
| topic | triazole «one-pot» synthesis molecular docking antistaphylococcal activity |
| url | https://www.mdpi.com/1424-8247/18/1/83 |
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