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Synthesis,in vitro antifungal activity and molecular modeling studies of new mannich bases derived from lawsone

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 and Greco, Sandro J. 2016. Synthesis,in vitro antifungal activity and molecular modeling studies of new mannich bases derived from lawsone. Journal of the Brazilian Chemical Society 27 (11) , pp. 2127-2140. 10.5935/0103-5053.20160104

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Sociedade Brasileira de Química, SBQ
ISSN: 0103-5053
Last Modified: 08 Jul 2019 12:27
URI: http://orca.cf.ac.uk/id/eprint/122290

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