Design and Synthesis of Verlamelin A Derivatives with Antifungal Activity against Alternaria spp.

Verlamelin A is a macrocyclic antifungal depsipeptide. In this study, a series of derivatives (1a-15a, 17a, 1b- 17b) were developed by replacing the l-Gln residue in verlamelin A with other proteinogenic l-amino acids. Biological evaluation revealed that compound 8b, substituted with an l-Thr residue, exhibited enhanced antifungal activity and an expanded spectrum against four plant pathogens─Alternaria alternata, Alternaria solani, Alternaria tenuissima, and Alternaria longipes─with minimum inhibitory concentration (MIC) values ranging from 4 to 32 μg/mL. Compound 12b, substituted with an l-Glu residue, showed antifungal activity against A. alternata, A. solani, and A. longipes, with MIC values ranging from 2 to 64 μg/mL. Both compounds demonstrated dose-dependent inhibitory effects on the mycelial growth of A. tenuissima and A. alternata, respectively. Structure-activity relationship studies indicated that compounds with the R configuration at the C-5 position of the tetradecanoic acid moiety exhibited broader spectrum of activity and greater potency than their S-configured counterparts. In vivo fruit infection assays showed that compounds 8b and 12b possessed curative efficacy, protecting tomatoes and apples from damage caused by these pathogens. With low toxicity, compounds 8b and 12b represent promising lead compounds for further development as antifungal agents to combat pathogens in agriculture.