Synthesis, in vitro Antifungal Activity and Molecular Modeling Studies of New Mannich Bases Derived from Lawsone

• Published in: Journal of the Brazilian Chemical Society Vol. 27; no. 11; pp. 2127 - 2140
• Main Authors: Allochio Filho, João F., Roldi, Larissa L., Delarmelina, Maicon, Fiorot, Rodolfo G., Andrade, Jessica T., Aleixo, Álan A., Carvalho, Rafaella S., Araújo, Marcelo G. F., Ferreira, Jaqueline M. S., Taranto, Alex G., Romão, Wanderson, Greco, Sandro J.
• Format: Journal Article
• Language: English
• Published: Sociedade Brasileira de Química 01-11-2016
• Subjects: CHEMISTRY, MULTIDISCIPLINARY; docking; Mannich bases; lawsone; antifungal activity
• ISSN: 0103-5053; 1678-4790
• DOI: 10.5935/0103-5053.20160104

Hydroxynaphthoquinones such as lawsone (2-hydroxy-1,4-naphthoquinone) have proven to be effective antifungal agents. These compounds were tested for antifungal activity against yeast standard and clinical strains by the broth microdilution method. Among the synthetic lawsone derivatives, 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione showed high activity against Candida albicans ATCC 10231, with minimal inhibitory concentrations (MICs) and minimal fungicidal concentrations (MFCs) ranging from 20 to 330 and from 80 to 330 µg mL-1, respectively. Moreover, they also showed a mechanism of action on exogenous ergosterol. Therapeutic concentrations (CC50) of 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione were 52.81, 52.58 and 85.94 µg mL-1, respectively, which can be considered moderate or low. In addition, docking studies showed that these compounds had similar binding energy to standard ketoconazole, which are recognized as the molecular target by van der Waals interactions. Furthermore, they are under Lipinski's rule of 5 with a druglikeness score better than ketoconazole and nystatin. These findings suggest that 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione have potential as leading compounds against human fungal infections.