Department of Organic Chemistry and Drug Technology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland.
Unique Application Model Laboratory, Department of Pharmaceutical Microbiology and Parasitology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland.
Int J Mol Sci. 2023 Feb 3;24(3):2997. doi: 10.3390/ijms24032997.
The microbial, biofilm-based infections of chronic wounds are one of the major challenges of contemporary medicine. The use of topically administered antiseptic agents is essential to treat wound-infecting microorganisms. Due to observed microbial tolerance/resistance against specific clinically-used antiseptics, the search for new, efficient agents is of pivotal meaning. Therefore, in this work, 15 isoxazole derivatives were scrutinized against leading biofilm wound pathogens and , and against fungus. For this purpose, the minimal inhibitory concentration, biofilm reduction in microtitrate plates, modified disk diffusion methods and antibiofilm dressing activity measurement methods were applied. Moreover, the cytotoxicity and cytocompatibility of derivatives was tested toward wound bed-forming cells, referred to as fibroblasts, using normative methods. Obtained results revealed that all isoxazole derivatives displayed antimicrobial activity and low cytotoxic effect, but antimicrobial activity of two derivatives, 2-(cyclohexylamino)-1-(5-nitrothiophen-2-yl)-2-oxoethyl 5-amino-3-methyl-1,2-oxazole-4-carboxylate () and 2-(benzylamino)-1-(5-nitrothiophen-2-yl)-2-oxoethyl 5-amino-3-methyl-1,2-oxazole-4-carboxylate (), was noticeably higher compared to the other compounds analyzed, especially with regard to , with a minimal inhibitory concentration more than x1000 lower compared to the remaining derivatives. The and derivatives were able to reduce more than 90% of biofilm-forming cells, regardless of the species, displaying at the same time none () or moderate () cytotoxicity against fibroblasts and high () or moderate () cytocompatibility against these wound cells. Therefore, taking into consideration the clinical demand for new antiseptic agents for non-healing wound treatment, seems to be a promising candidate to be further tested in advanced animal models and later, if satisfactory results are obtained, in the clinical setting.
慢性伤口的微生物、生物膜相关感染是当代医学面临的主要挑战之一。局部应用防腐剂对于治疗感染伤口的微生物至关重要。由于观察到微生物对特定临床使用防腐剂的耐受性/耐药性，因此寻找新的、有效的防腐剂具有重要意义。因此，在这项工作中，研究了 15 种异噁唑衍生物对主要生物膜伤口病原体 和 ，以及真菌 的抑制作用。为此，应用了最小抑菌浓度、微量滴定板上的生物膜减少、改良的圆盘扩散方法和抗菌膜敷料活性测量方法。此外，还使用常规方法测试了衍生物对伤口形成细胞（称为成纤维细胞）的细胞毒性和细胞相容性。结果表明，所有异噁唑衍生物均具有抗菌活性和低细胞毒性，但两种衍生物 2-（环己氨基）-1-（5-硝基噻吩-2-基）-2-氧代乙基 5-氨基-3-甲基-1,2-噁唑-4-羧酸酯（）和 2-（苄基氨基）-1-（5-硝基噻吩-2-基）-2-氧代乙基 5-氨基-3-甲基-1,2-噁唑-4-羧酸酯（）的抗菌活性明显高于其他分析的化合物，尤其是对 ，其最小抑菌浓度比其余衍生物低超过 x1000。和 衍生物能够减少超过 90%的生物膜形成细胞，无论物种如何，同时对成纤维细胞的细胞毒性为无（）或中度（），对这些伤口细胞的细胞相容性为高（）或中度（）。因此，考虑到对非愈合伤口治疗用新型防腐剂的临床需求， 似乎是一个有前途的候选物，将在更先进的动物模型中进一步测试，如果获得满意的结果，将在临床环境中进行测试。
