{"title":"苯基噻吩结构三唑类抗真菌药物的设计、合成和生物活性评价","authors":"","doi":"10.1016/j.bioorg.2024.107785","DOIUrl":null,"url":null,"abstract":"<div><p>Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using <strong>Iodiconazole</strong> as the lead compound. Among them, compound <strong>19g</strong> is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against <em>Candida albicans</em>, <em>Cryptococcus neoformans</em>, and <em>Aspergillus</em>, with a MIC<sub>80</sub> value of 0.0625 μg/mL. In addition, compounds <strong>19e</strong>, <strong>19f</strong>, <strong>19g</strong>, <strong>19h</strong>, <strong>19i</strong> and <strong>19k</strong> exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC<sub>80</sub> values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound <strong>19g</strong> had optimal <em>in vitro</em> antifungal activity, we selected <strong>19g</strong> for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound <strong>19g</strong> on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound <strong>19g</strong> on the filamentation of <em>Candida albicans</em> and determined the mechanism of action by sterol composition analysis.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, synthesis and bioactivity evaluation of triazole antifungal drugs with phenylthiophene structure\",\"authors\":\"\",\"doi\":\"10.1016/j.bioorg.2024.107785\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using <strong>Iodiconazole</strong> as the lead compound. Among them, compound <strong>19g</strong> is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against <em>Candida albicans</em>, <em>Cryptococcus neoformans</em>, and <em>Aspergillus</em>, with a MIC<sub>80</sub> value of 0.0625 μg/mL. In addition, compounds <strong>19e</strong>, <strong>19f</strong>, <strong>19g</strong>, <strong>19h</strong>, <strong>19i</strong> and <strong>19k</strong> exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC<sub>80</sub> values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound <strong>19g</strong> had optimal <em>in vitro</em> antifungal activity, we selected <strong>19g</strong> for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound <strong>19g</strong> on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound <strong>19g</strong> on the filamentation of <em>Candida albicans</em> and determined the mechanism of action by sterol composition analysis.</p></div>\",\"PeriodicalId\":257,\"journal\":{\"name\":\"Bioorganic Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-09-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0045206824006904\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824006904","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Design, synthesis and bioactivity evaluation of triazole antifungal drugs with phenylthiophene structure
Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using Iodiconazole as the lead compound. Among them, compound 19g is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus, with a MIC80 value of 0.0625 μg/mL. In addition, compounds 19e, 19f, 19g, 19h, 19i and 19k exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC80 values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound 19g had optimal in vitro antifungal activity, we selected 19g for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound 19g on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound 19g on the filamentation of Candida albicans and determined the mechanism of action by sterol composition analysis.
期刊介绍：
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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