Abstract
Aim: An urgent need for the development of antibiotics with novel structures and unexploited targets. Materials & methods: Racemic chuangxinmycin was obtained via a novel synthesis route. Chiral preparative chromatography was used to separate chuangxinmycin from its epimers, and four stereoisomers were obtained. Fourteen derivatives were synthesized and their antibacterial activities were evaluated against Escherichia coli and Staphylococcus aureus. Results: Synthesized (3S, 4R)-chuangxinmycin showed antibacterial activity against S. aureus with minimum inhibitory concentration of 4–8 μg/ml (17.2–34.3 μM), which were consistent with the antibacterial activity of chuangxinmycin obtained by fermentation. The minimum inhibitory concentrations of other stereoscopic chuangxinmycin species and chuangxinmycin derivatives were >128 μg/ml. Conclusion: Results indicate that the antibacterial activity of chuangxinmycin is dependent on the stereoselectivity of structures, and that the electron cloud density and amphipathic properties of chuangxinmycin have little effect on its antibacterial activity.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Newer antibacterial drugs for a new century. Expert Opin. Invest. Drugs 19, 215–234 (2010). • Very important report regarding the current situation of multidrug resistance.
- 2. . Antimicrobials: new solutions badly need-editorial overview. Curr. Opin. Microbiol. 5(5), 463–465 (2002).
- 3. . Structural determination of chuangxinmycin. Hua Xue Xue Bao 34(2), 129–132 (1976); Chem. Abstr. 87, 165948z (1977); Sci. Sin. 20, 106 (1977); Chem. Abstr. 87, 98565g (1977).
- 4. The crystal structure of chuangmycin. Ke Xue Tong Bao 8, 350 (1980).
- 5. The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase. Bioorg. Med. Chem. Lett. 12, 3171–3174 (2002). • Very important report regarding the structure–activity relationship of chuangxinmycin.
- 6. . Total synthesis of the unique indole alkaloid chuangxinmycin. Application of nitro group displacement reactions in organic synthesis. J. Am. Chem. Soc. 102(3), 1165–1166 (1980).
- 7. . Synthetic studies in the Indole series. Preparation of the unique antibiotic alkaloid chuangxinmycin by a nitro group displacement reaction. J. Am. Chem. Soc. 104(26), 7622–7626 (1982).
- 8. . A new, general entry to 4-substituted indoles. Synthesis of (S)-(-)-pindolo and (±)-chuangxinmycin. Tetrahedron Lett. 34(3), 489–492 (1993).
- 9. . New total synthesis of (±)-, (−)-, (+)-chuangxinmycins. Terrahedron 57, 10055–10062 (2001).
- 10. . Synthesis of chuangxinmycin analogues. Chin. J. Pharm. 139(2), 17–21 (1984). • Very important report regarding the structure–activity relationship of chuangxinmycin.
- 11. . Synthesis of chuangxinmycin analogues. Heterocycles 26(7), 1743–1746 (1987). • Very important report regarding the structure–activity relationship of chuangxinmycin.
- 12. . Synthesis and antibacterial activity evaluation of chuangxinmycin prodrugs. Chin. Med. Biotechnol. 11(4), 314–318 (2016).
- 13. . The necessary nitrogen atom: a versatile high-impact design element for multiparameter optimization. J. Med. Chem. 60(9), 3552–3579 (2017). •• Very important report regarding the design strategy of derivatives of chuangxinmycin.
- 14. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545(7654), 299–304 (2017). •• Very important report regarding the design strategy of derivatives of chuangxinmycin.
- 15. . A new total synthesis of chuangxinmycin and the study of its stereoisomers. Acta Pharmaceutica Sinica 22(9), 671–678 (1987).