de Araújo Rodrigo S A, Guerra Felipe Q S, de O Lima Edeltrudes, de Simone Carlos A, Tavares Josean F, Scotti Luciana, Scotti Marcus T, de Aquino Thiago M, de Moura Ricardo O, Mendonça Francisco J B, Barbosa-Filho José M
Pharmaceutical Science Department, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil.
Int J Mol Sci. 2013 Jan 10;14(1):1293-309. doi: 10.3390/ijms14011293.
The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 µg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO(2) and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2(cv) of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.
机会性真菌感染的发病率增加，加上对目前使用的抗真菌药物的耐药性增强，凸显了对新解决方案的需求。在本研究中，对24种香豆素衍生物进行了体外筛选，以检测其对曲霉菌株的抗真菌活性。一些化合物表现出显著的抗真菌活性，最低抑菌浓度（MIC）值在16至32μg/mL之间。构效关系（SAR）研究表明，O-取代对抗真菌活性至关重要。研究还表明，短脂肪链和/或吸电子基团（NO(2)和/或乙酸酯）的存在有利于活性。在计算最低未占分子轨道（LUMO）密度时，使用密度泛函理论（DFT）证实了这些发现。在主成分分析（PCA）中，两个显著的主成分（PC）解释了总方差的60%以上。最佳偏最小二乘回归（PLS）模型显示r2为0.86，q2（cv）为0.64，证实了构效关系观察结果，并表明活性化合物的探针N1相互作用更强。由TIP相关图生成的描述符证明了分子形状对抗真菌活性的重要性。
