Shabelnyk Kostiantyn, Fominichenko Alina, Antypenko Oleksii, Gaponov Olexandr, Koptieva Svitlana, Shyshkina Svitlana, Voskoboinik Oleksii, Okovytyy Sergiy, Kovalenko Serhii, Oksenych Valentyn, Kamyshnyi Oleksandr
Department of Pharmaceutical, Organic and Bioorganic chemistry, Zaporizhzhia State Medical and Pharmaceutical University, 69000 Zaporizhzhia, Ukraine.
Bacteriological Laboratory, Zaporizhzhia Regional Hospital, 69600 Zaporizhzhia, Ukraine.
Pharmaceuticals (Basel). 2025 Jan 11;18(1):83. doi: 10.3390/ph18010083.
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-[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.
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.
A significant part of the obtained compounds showed high antibacterial activity against (MIC: 10.1-62.4 µM) and 5-bromo-2-(3-(furan-3-yl)-1-1,2,4-triazol-5-yl)aniline and 5-fluoro-2-(3-(thiophen-3-yl)-1-1,2,4-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-[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.
Obtained [2-(3-R-1-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antistaphylococcal activity and deserve for further detailed study as effective antibacterial agents.
在耐药时代，设计并寻找具有窄谱活性的新型“小分子”，使其以高选择性和最小副作用靶向特定细菌的蛋白质或酶，仍然是药物化学的一个紧迫问题。在这方面，我们开发并成功实施了一种寻找新型杂合分子的策略，即鲜为人知的[2-(3-R-1-[1,2,4]-三唑-5-基)苯基]胺。它们可作为“构建模块”，并允许将某些结构基序引入所需的最终产物中，以增强抗葡萄球菌效果。
后者的“一锅法”合成基于将取代的4-肼基喹唑啉或取代的2-氨基苯腈与羧酸衍生物转化为目标产物。使用分子对接研究并讨论了合成化合物（DNA促旋酶抑制剂）可能的分子机制，并证实了对其抗葡萄球菌活性的进一步研究。
所获得的化合物中有很大一部分对金黄色葡萄球菌显示出高抗菌活性（MIC：10.1 - 62.4 μM），5-溴-2-(3-(呋喃-3-基)-1-1,2,4-三唑-5-基)苯胺和5-氟-2-(3-(噻吩-3-基)-1-1,2,4-三唑-5-基)苯胺的MIC分别为5.2和6.1 μM，接近参考药物“环丙沙星”的效果强度（MIC：4.7 μM）。进行的构效关系（SAR）和药物代谢动力学（ADME）分析证实了这些化合物进一步结构修饰的前景。所获得的[2-(3-R-1-[1,2,4]-三唑-5-基)苯基]胺显示出显著的抗菌活性，作为有效的抗葡萄球菌剂值得进一步进行结构修饰和详细研究。SAR分析表明，三唑环第三位存在环烷基或富电子杂环片段对于所获得化合物的抗菌活性至关重要。同时，在苯胺部分引入甲基导致活性增强。在苯胺片段中引入卤素对抗葡萄球菌活性水平有模糊的影响，并且取决于第三位取代基的性质。
所获得的[2-(3-R-1-[1,2,4]-三唑-5-基)苯基]胺显示出显著的抗葡萄球菌活性，作为有效的抗菌剂值得进一步详细研究。
