Abstract: 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 (NO2 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 q2cv 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.
Keywords: coumarin derivatives; antifungal activity; Aspergillus sp.; structure-activity relationships (SAR); molecular modeling; principal component analysis (PCA); partial least squares regression (PLS); density functional theory (DFT)
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de Araújo, R.S.A.; Guerra, F.Q.S.; de O. Lima, E.; de Simone, C.A.; Tavares, J.F.; Scotti, L.; Scotti, M.T.; de Aquino, T.M.; de Moura, R.O.; Mendonça, F.J.B.; Barbosa-Filho, J.M. Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity. Int. J. Mol. Sci. 2013, 14, 1293-1309.
de Araújo RSA, Guerra FQS, de O. Lima E, de Simone CA, Tavares JF, Scotti L, Scotti MT, de Aquino TM, de Moura RO, Mendonça FJB, Barbosa-Filho JM. Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity. International Journal of Molecular Sciences. 2013; 14(1):1293-1309.
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. 2013. "Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity." Int. J. Mol. Sci. 14, no. 1: 1293-1309.