title: Anti-trichophyton activity of protocatechuates and their synergism with fluconazole.
abstract: Dermatophytosis and superficial mycosis are a major global public health problem that affects 20-25% of the world's population. The increase in fungal resistance to the commercially available antifungal agents, in conjunction with the limited spectrum of action of such drugs, emphasises the need to develop new antifungal agents. Natural products are attractive prototypes for antifungal agents due to their broad spectrum of biological activities. This study aimed to verify the antifungal activity of protocatechuic acid, 3,4-diacetoxybenzoic, and fourteen alkyl protocatechuates (3,4-dihydroxybenzoates) against Trichophyton rubrum and Trichophyton mentagrophytes and to further assess their activities when combined with fluconazole. Susceptibility and synergism assays were conducted as described in M38-A2 (CLSI), with modifications. Three strains of Trichophyton rubrum and three strains of Trichophyton mentagrophytes were used in this work. The pentyl, hexyl, heptyl, octyl, nonyl, and decyl protocatechuates showed great fungicidal effects, with minimum inhibitory concentration (MIC) values ranging from 0.97 to 7.8 mg/L. Heptyl showed a synergistic activity (FIC index = 0.49), reducing the MIC of fluconazole by fourfold. All substances tested were safe, especially the hexyl, heptyl, octyl, and nonyl compounds, all of which showed a high selectivity index, particularly in combination with fluconazole. These ester associations with fluconazole may represent a promising source of prototypes in the search for anti-Trichophyton therapeutic agents.
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Luciana Arantes
authors.identifier: 0000-0001-6560-4049
authors.initials: LA
authors.lastname: Soares
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Fernanda Patrícia
authors.initials: FP
authors.lastname: Gullo
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Janaina de Cássia Orlandi
authors.initials: Jde C
authors.lastname: Sardi
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Nayla de Souza
authors.identifier: 0000-0003-3248-5180
authors.initials: Nde S
authors.lastname: Pitangui
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Caroline Barcelos
authors.initials: CB
authors.lastname: Costa-Orlandi
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Sangalli-Leite
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Liliana
authors.initials: L
authors.lastname: Scorzoni
authors.affiliation: Institute of Chemistry, UNESP, Rua Professor Francisco Degni 55, 14800-900 Araraquara, SP, Brazil.
authors.forename: Luis Octávio
authors.initials: LO
authors.lastname: Regasini
authors.affiliation: Institute of Chemistry, UNESP, Rua Professor Francisco Degni 55, 14800-900 Araraquara, SP, Brazil.
authors.forename: Maicon Segalla
authors.initials: MS
authors.lastname: Petrônio
authors.affiliation: Institute of Chemistry, UNESP, Rua Professor Francisco Degni 55, 14800-900 Araraquara, SP, Brazil.
authors.forename: Patrícia Fernanda
authors.initials: PF
authors.lastname: Souza
authors.affiliation: Institute of Chemistry, UNESP, Rua Professor Francisco Degni 55, 14800-900 Araraquara, SP, Brazil.
authors.forename: Dulce Helena Siqueira
authors.initials: DH
authors.lastname: Silva
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Maria José Soares
authors.initials: MJ
authors.lastname: Mendes-Giannini
authors.affiliation: Laboratory of Clinical Mycology, Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP, Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil ; Department of Clinical Mycology, Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista (UNESP), Rodovia Araraquara-Jaú, Km 1, 14801-902 Araraquara, SP, Brazil.
authors.forename: Ana Marisa
authors.identifier: 0000-0002-2115-8988
authors.initials: AM
authors.lastname: Fusco-Almeida