摘要
目的基于先导化合物伊曲康唑,设计合成系列衍生物(6a-6k),旨在通过体外抗真菌活性筛选,获得高效、低毒且选择性高的候选化合物,并探讨其构效关系。方法采用药物化学优化策略,设计合成11个新型伊曲康唑衍生物。通过微量液基稀释法测定目标化合物的体外抗真菌活性,结合斑点实验评估抗菌谱,系统考察化合物对真菌菌丝生长和生物被膜形成的抑制作用,运用Swiss ADME工具预测化合物的药代动力学特性,对化合物进行综合评估。结果所有目标化合物均表现出显著的体外抗真菌活性。其中,化合物6c和6f表现出最优活性,对多种致病真菌的MIC80值低至0.0156μg/mL。值得注意的是,化合物6c对耐药菌株亦表现出良好抑制效果(MIC80=0.25μg/mL)。在0.0625μg/mL浓度下,化合物6c能有效抑制白念珠菌SC5314的菌丝形成;在0.25μg/mL时,化合物6c对早期和成熟生物被膜的形成均有显著影响。结论化合物6c对包括耐药白念珠菌在内的菌株具有广谱抗真菌活性,同时能抑制菌丝和生物被膜的形成,具备作为抗真菌药物候选分子的进一步研究价值。
Objective Based on itraconazole as the lead compound,a series of derivatives(6a-6k)were designed and synthesized to identify highly potent,low-toxicity,and selective antifungal candidates through in vitro screening,while investigating their structure-activity relationships(SAR).Methods Using medicinal chemistry optimization strategies,11 novel itraconazole derivatives were designed and synthesized.The in vitro antifungal activity of the target compounds was determined by the microbroth dilution method,while their antifungal spectrum was assessed via spot assay.The inhibitory effects on fungal hyphae formation and biofilm growth were systematically evaluated.Additionally,we employ Swiss ADME tools to predict the pharmacokinetic properties of compounds,thereby conducting a comprehensive assessment of the compounds.Results All target compounds exhibited significant antifungal activity.Notably,compounds 6c and 6f demonstrated the most potent efficacy,with MIC80 values as low as 0.0156μg/mL against multiple pathogenic fungi.Importantly,compound 6c also exhibited strong inhibitory activity against drug-resistant strains(MIC80=0.25μg/mL).At a concentration of 0.0625μg/mL,compound 6c effectively suppressed hyphae formation in Candida albicans(SC5314).In addition,at the concentration of 0.25μg/mL,compound 6c has a significant effect on both early and mature biofilm formation.Conclusion Compound 6c exhibits broad-spectrum antifungal activity,including potent inhibition against drug-resistant strains,while also inhibiting hyphae and biofilm formation.It holds potential for further investigation as a candidate antifungal drug molecule.
作者
赵萌萌
方文捷
柴晓云
潘炜华
廖万清
王培培
ZHAO Mengmeng;FANG Wenjie;CHAI Xiaoyun;PAN Weihua;LIAO Wanqing;WANG Peipei(College of Food Science and Technology,Shanghai Ocean University,Shanghai 201306,China;Dermatology Department,the Second Affiliated Hospital,Naval Medical University,Shanghai 200003,China;Department of Organic Chemistry,School of Pharmacy,Navy Medical University,Shanghai 200433,China;Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area,Shanghai 201306,China)
出处
《中国真菌学杂志》
2025年第6期568-575,共8页
Chinese Journal of Mycology
基金
临港新片区海洋生物医药科技创新型平台科创基金(RWS-2024-002)。
