Department of Molecular Microbiology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland.
Department of Organic Chemistry, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin, Chodźki 4a, 20-093, Lublin, Poland.
Sci Rep. 2024 Feb 12;14(1):3521. doi: 10.1038/s41598-024-54025-9.
Nowadays, dermatophyte infections are relatively easy to cure, especially since the introduction of orally administered antifungals such as terbinafine and itraconazole. However, these drugs may cause side effects due to liver damage or their interactions with other therapeutics. Hence, the search for new effective chemotherapeutics showing antidermatophyte activity seems to be the urge of the moment. Potassium salts of N-acylhydrazinecarbodithioates are used commonly as precursors for the synthesis of biologically active compounds. Keeping that in mind, the activity of a series of five potassium N-acylhydrazinecarbodithioates (1a-e) and their aminotriazole-thione derivatives (2a-e) was evaluated against a set of pathogenic, keratinolytic fungi, such as Trichophyton ssp., Microsporum ssp. and Chrysosporium keratinophilum, but also against some Gram-positive and Gram-negative bacteria. All tested compounds were found non-toxic for L-929 and HeLa cells, with the IC and IC values assessed in the MTT assay above 128 mg/L. The compound 5-amino-3-(naphtalene-1-yl)-4,5-dihydro-1H-1,2,4-triazole-5-thione (2d) was found active against all fungal strains tested. Scanning Electron Microscopy (SEM) revealed inhibition of mycelium development of Trichophyton rubrum cultivated on nail fragments and treated with 2d 24 h after infection with fungal spores. Transmission Electron Microscopy (TEM) observation of mycelium treated with 2d showed ultrastructural changes in the morphology of germinated spores. Finally, the RNA-seq analysis indicated that a broad spectrum of genes responded to stress induced by the 2d compound. In conclusion, the results confirm the potential of N-acylhydrazinecarbodithioate derivatives for future use as promising leads for new antidermatophyte agents development.
如今，皮肤癣菌感染相对容易治愈，尤其是引入特比萘芬和伊曲康唑等口服抗真菌药物之后。然而，这些药物可能会因肝损伤或与其他治疗药物的相互作用而引起副作用。因此，寻找具有抗皮肤癣菌活性的新有效化学治疗药物似乎是当务之急。N-酰基腙碳二硫代酸的钾盐通常用作合成具有生物活性的化合物的前体。考虑到这一点，评估了一系列五种钾 N-酰基腙碳二硫代酸盐（1a-e）及其氨基三唑-硫酮衍生物（2a-e）对一组致病的角蛋白分解真菌（如 Trichophyton ssp.、Microsporum ssp. 和 Chrysosporium keratinophilum）以及一些革兰氏阳性和革兰氏阴性细菌的活性。所有测试的化合物都被发现对 L-929 和 HeLa 细胞没有毒性，在 MTT 测定中，IC 和 IC 值评估值均高于 128mg/L。化合物 5-氨基-3-（萘-1-基）-4,5-二氢-1H-1,2,4-三唑-5-硫酮（2d）对所有测试的真菌菌株均表现出活性。扫描电子显微镜（SEM）显示，在感染真菌孢子 24 小时后，用 2d 处理培养在指甲碎片上的红色毛癣菌的菌丝体发育受到抑制。用 2d 处理的菌丝体的透射电子显微镜（TEM）观察显示出发芽孢子形态的超微结构变化。最后，RNA-seq 分析表明，广泛的基因对 2d 化合物诱导的应激产生反应。总之，这些结果证实了 N-酰基腙碳二硫代酸衍生物具有作为新型抗皮肤癣菌药物开发有前途的先导物的潜力。
