Design, synthesis and antifungal evaluation of borrelidin derivatives

[Display omitted] •Synthesis and antifungal evaluation of forty-seven borrelidin analogs.•Fragment -OCH2CH2N- was essential for antifungal activity.•3b exhibited activity against C. albicans which was insensitive to borrelidin.•Compared with borrelidin, 4n and 4r presented extra activity against A. fumigatus.•Carboxyl substituents in borrelidin existed extra interaction with fungal ThrRS. Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5-phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 μg/mL, respectively). Furthermore, compounds 4n and 4r presented better antifungal activity against Aspergillus fumigatus with 12.5 μg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH2CH2N- had an important effect on the antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic fungal threonyl-tRNA synthetase (ThrRS).