Synthesis and antifungal activity of terpenyl-1,4-naphthoquinone and 1,4-anthracenedione derivatives

• Published in: European journal of medicinal chemistry 2013-09, Vol.67, p.19-27
• Main Authors: Castro, Ma Ángeles, Gamito, Ana Ma, Tangarife-Castaño, Verónica, Zapata, Bibiana, Miguel del Corral, José Ma, Mesa-Arango, Ana C., Betancur-Galvis, Liliana, San Feliciano, Arturo
• Format: Article
• Language: English
• Subjects: 1,4-Anthracenediones; Animals; Anthracenes - chemical synthesis; Anthracenes - chemistry; Anthracenes - pharmacology; Antifungal; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aspergillus - drug effects; Candida - drug effects; Cell Survival - drug effects; Cercopithecus aethiops; Diels–Alder; Dose-Response Relationship, Drug; Fusarium - drug effects; Microbial Sensitivity Tests; Molecular Structure; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Prenyl-1,4-naphthoquinones; Structure-Activity Relationship; Time-kill curves; Trichophyton - drug effects; Vero Cells
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.06.018

The antifungal evaluation of twenty seven simple and heterocycle-fused prenyl-1,4-naphthoquinones and 1,4-anthracenediones was performed in vitro against human pathogenic yeasts (Candida spp.) and filamentous fungi (Aspergillus spp., Fusarium spp., and Trichophyton spp.). The synthetic strategy used to obtain the quinone derivatives was initially based on the Diels–Alder cycloaddition between myrcene and several p-benzoquinone derivatives, followed by cyclisation of the prenyl side chain in the case of anthracene-1,4-diones. The most promising compounds, displaying MIC values in the low μg/mL range, were those bearing one or two chlorine atoms attached to the quinone ring. Time-kill curves determined for the most potent compounds showed their fungistatic mode of action similar to that of itraconazole. MIC in μg/mL (Tm: Trycophyton mentagrophytes; Tr: Trichophyton rubrum; Ck: Candida krusei; Cl: C. lusitaniae, Afu: Aspergillus fumigatus). HSI: Highest selectivity index. [Display omitted] •Twenty seven 1,4-quinone derivatives were evaluated as antifungals.•Five compounds showed fair wide antifungal spectra.•Some of them showed MIC90 values  9–50, with respect to Vero cells.•Time-kill assays suggest a fungistatic behaviour.