Synthesis and in vitro antifungal activity evaluation of novel itraconazole derivatives

ZHAO Mengmeng; FANG Wenjie; CHAI Xiaoyun; PAN Weihua; LIAO Wanqing; WANG Peipei

doi:10.3969/j.issn.1673-3827.2025.06.002

Abstract：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 0.0156 μg/mL against multiple pathogenic fungi.Importantly,compound 6c also exhibited strong inhibitory activity against drug-resistant strains(MIC80=0.25 μg/mL).At a concentration of 0.0625 μg/mL,compound 6c effectively suppressed hyphae formation in Candida albicans(SC5314).In addition,at the concentration of 0.25 μg/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.