New antifungal ent-labdane diterpenes against Candida glabrata produced by microbial transformation of ent-polyalthic acid

Author(s)

de Sousa, Ingrid Pontes ^[1] ; Ferreira, Antonio Gilberto ^[2] ; Miller Crotti, Antonio Eduardo ^[3] ; dos Santos, Raquel Alves ^[4] ; Kiermaier, Josef ^[5] ; Kraus, Birgit ^[5] ; Heilmann, Joerg ^[5] ; Jacometti Cardoso Furtado, Niege Aracari ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Pharmaceut Sci, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Fed Sao Carlos, Chem Dept, Lab Nucl Magnet Resonance, Sao Carlos, SP - Brazil

^[3] Univ Sao Paulo, Sch Philosophy Sci & Languages Ribeirao Preto, Dept Chem, Ribeirao Preto, SP - Brazil

^[4] Univ Franca, Nucleus Res Sci & Technol, Franca, SP - Brazil

^[5] Univ Regensburg, Fac Chem & Pharm, Dept Pharmaceut Biol, Regensburg - Germany

• Document type: Journal article
• Source: BIOORGANIC CHEMISTRY; v. 95, JAN 2020.
• Web of Science Citations: 0

Abstract

Candida glabrata, the most common non-albicans Candida species and one of the primary causes of candidemia, exhibits decreased susceptibility to azoles and more recently to echinocandins. Polyalthic acid 1, a furan diterpene, has been shown promising biological potential and in this study ent-polyalthic acid derivatives with antifungal activity against Candida glabrata were produced by microbial transformation. Incubation of 1 with Aspergillus brasiliensis afforded two known (compounds 5 and 10) and eight new derivatives (compounds 2-4, 6-9 and 11). The most common reaction was hydroxylation, but isomerization of the double bond and acetylation were also detected. None of the tested compounds showed cytotoxicity against HeLa, MCF-7 and MCF-10A cell lines showing IC50 values ranging from 62.6 mu M to > 500 mu M. Compounds 1, 5, 6, 8 and 11 showed fungistatic effects (ranging from 34.1 mu M to 39.5 mu M) on C. glabrata at lower concentrations than fluconazole (163.2 mu M). Compounds 1, 6 and 8 were more potent fungicides (ranging from 79.0 to 143.6 mu M) than fluconazole, which showed fungicidal effect at concentrations higher than 163.2 mu M. These results suggest that ent-polyalthic acid and some of its derivatives could be used as lead compounds to develop new antifungal agents. (AU)

• FAPESP's process: 11/13630-7 - Chemical and pharmacological validation of extracts and active compounds of Copaifera species
• Grantee: Jairo Kenupp Bastos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/25201-7 - In vitro studies of bioaccessibility, intestinal transportation and biotransformation of ent-hardwickiic and ent-polyalthic acids from Copaifera pubiflora and Copaifera duckei oil resins
• Grantee: Niege Araçari Jacometti Cardoso Furtado
• Support Opportunities: Regular Research Grants