Design, synthesis and antifungal evaluation of borrelidin derivatives. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Hu, Caijuan; Su, Hao; Luo, Jinghan; Han, Li; Liu, Qingyin; Wu, Wenxi; Mu, Yu; Guan, Peipei; Sun, Tiemin; Huang, Xueshi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 23/24(2018)
• Page Start: 6035
• Page End: 6049
• Publication Date: 2018-12-15
• Subjects: Borrelidin -- Synthesis -- Antifungal activity -- Structure-activity relationships -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.11.005
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Synthesis and antifungal evaluation of forty-seven borrelidin analogs. Fragment -OCH2 CH2 N- was essential for antifungal activity. 3b exhibited activity against C. albicans which was insensitive to borrelidin. Compared with borrelidin, 4n and4r presented extra activity against A. fumigatus . Carboxyl substituents in borrelidin existed extra interaction with fungal ThrRS. Abstract: 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, compound3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 μg/mL, respectively). Furthermore, compounds4n and4r 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 -OCH2 CH2 N- 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).