Asymmetric synthesis and antifungal evaluation of arylalkylamine-functionalized β-substituted (s)-α-alanine analogues

In the present study, a series of novel arylalkylamine-containing unnatural α-amino acids were synthesized through the stereoselective nucleophilic addition of benzylamine derivatives to a chiral Ni(II) complex of dehydroalanine derived from the (S)-BPB auxiliary. The reactions proceeded with high diastereoselectivity (92–95% de) and afforded the corresponding α-amino acids in moderate to good yields with high enantiomeric purity (57–98% ee). The synthesized compounds were evaluated for their antifungal activity against Aspergillus species, including Aspergillus flavus , Aspergillus fumigatus , and Aspergillus candidus . All tested compounds exhibited dose-dependent antifungal effects, although substantial differences in activity were observed depending on the nature of the arylalkyl substituent. Among the investigated derivatives, compounds 4d and 4e demonstrated the most pronounced antifungal activity, producing growth inhibition of up to 67.86% and 68.75%, respectively, at the highest tested concentration. Their activity approached that of the reference antifungal drug Fluconazole. These findings identify compounds 4d and 4e as promising lead structures for the development of novel antifungal agents targeting pathogenic Aspergillus species.