Synthesis and Antibacterial Activity of Ursolic Acid Derivatives

Author(s): Xiaoyuan Song, Junfang Li, Yimin Wang, Ganjun Yuan, Shan Lai, Houqin Yi, Pingyi Li

To obtained natural products with remarkable antibacterial activities, three 3-amino substituted (UA) derivatives 2, 3 and 4 were designed and synthesized, and their antibacterial activity were assayed using broth microdilution method. Compared to UA, there three derivatives present higher antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA) with the minimum inhibitory concentrations of 16 to 32 μg/mL. Furthermore, their cytotoxicities to human hepatoma cell (BEL-7402) were evaluated using MTT method, and the results indicated that their derivatives had no toxicity (IC50 value was larger than 10 μM), while UA presented a certain cytotoxicity.

Ursolic Acid, Antibacterial Activity, Synthesis, Structural Modification, Mic, Mtt

1. Alinezhad H, Tajbakhsh M, Salehian F. 2009. Reductive amination of aldehydes and ketones to their corresponding amines with N-methylpyrrolidine zinc borohydride. Tetrahedron Lett. 50(6):659-661.
2. Ana LM, María Eva GT, Marco C, Francisco P. 2012. Antinociceptive effectiveness of triterpenes from rosemary in visceral nociception. J Ethnopharmacol. 142(1): 28-34.
3. Chen L, Qiu W, Tang J, Wang ZF, He SH. 2011. Synthesis and bioactivity of novel nitric oxide-releasing ursolic acid derivatives. Chin Chem Lett. 22(4):413-416.
4. Deng SL, Baglin I, Nour M, Flekhter O, Vita C, Cavé C. 2007. Synthesis of ursolic phosphonate derivatives as potential anti-HIV agents. Phosphorus Sulfur Silicon. 182(5):951-967.
5. Fumiko A, Tatsuo Y, Tsuneatsu N, Junei K, Hikaru O, Hiroo H, Hiroshige A. 2002. Ursolic acid as a trypanocidal constituent in rosemary. Biol Pharm Bull. 25(11):1485-1487.
6. Huang Y, Li M, Yu X, Yuan ZD. 2008. Application of Sodium triacetoxyborohydride (STAB-H) in reductive amination. Chin J Pharm. 39(9):695-701.
7. Isaber BL, Zorica S, Rosa QP, David AR, Jaroslava ŠG, Alberto FG, Antonio SC. 2014. Rosmarinus officinalis leaves as a natural source of bioactive compounds. Int J Mol Sci. 15(11):20585-20586.
8. Jiang W, Huang RZ, Zhang J, Guo T, Zhang MT, Huang XC, Zhang B, Liao ZX, Sun J, Wang HS. 2018. Discovery of antitumor ursolic acid long-chain diamine derivatives as potent inhibitors of NF-κB. BIOORG CHEM. 79:265-276.
9. Li JF, Wang YM, Yuan GJ, Li GH, Xu XJ, Song XY. 2019. Analyses on triterpene acids components in leaves of Rosemarinus officinalis and their inhibitory activities. J Plant Resour Environ. 28(1):115-117.
10. Li W, Zhang HX, Nie M, Wang W, Liu ZT, Chen CS, Chen HJ, Liu R, Baloch Z, Ma K. 2018. A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines. ONCOL LETT. 15(2):2323-2329.
11. Ma CM, Nakamura N, Miyashiro H, Hattroal M, Shimotohno K. 1998. Inhibiory effects of ursolic acid derivatives from cynomorium songaricum, and related triterpenes on human immunodeficiency viral protease. Phytother Res. 12(S1): S138-S142.
12. Ma CM, Nakamura N, Miyashiro H, Hattori M, Shimotohno K. 1999. Inhibiory effects of constituens from cynomorium songaricum and rejated triterpene derivatives on HIV-1 protease. Chem Pham Bull. 47(2):141-145.
13. Meng YQ, Liu D, Cai LL, Chen H, Cao B, Wang YZ. 2009. The synthesis of ursolic acid derivatives with cytotoxic activity and the investigation of their preliminary mechanism of action. Bioorg Med Chem. 17(2):848-854.
14. Simone F. Betulinic acid for cancer treatment and prevention. 2008. Int J Mol Sci. 9(6):1096-1107.
15. Zhang W, Hong D, Zhou YZ, Zhang Y, Shen Q, Li JY, Hu LH, Li J. 2006. Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake. Biochim Biophys Acta. 1760(10):1505-1512.
16. Xu XJ, Xu L, Yuan GJ, Wang YM, Qu YQ, Zhou MJ. 2018. Synergistic combination of two antimicrobial agents closing each other's mutant selection windows to prevent antimicrobial resistance. Sci Rep. 8(1):1-7