Synthesis and Biological Evaluation of Pentacyclic Triterpenoid Derivatives as Potential Novel Antibacterial Agents

Panpan Wu; Borong Tu; Jinfeng Liang; Shengzhu Guo; Nana Cao; Silin Chen; Zhujun Luo; Jiahao Li; Wende Zheng; Xiaowen Tang; Dongli Li; Xuetao Xu; Wenfeng Liu; Xi Zheng; Zhaojun Sheng; Adam Roberts; Kun Zhang; Weiqian David Hong

doi:10.1016/j.bioorg.2021.104692

Synthesis and Biological Evaluation of Pentacyclic Triterpenoid Derivatives as Potential Novel Antibacterial Agents

Panpan Wu, Borong Tu, Jinfeng Liang, Shengzhu Guo, Nana Cao, Silin Chen, Zhujun Luo, Jiahao Li, Wende Zheng, Xiaowen Tang, Dongli Li, Xuetao Xu, Wenfeng Liu, Xi Zheng, Zhaojun Sheng, Adam Roberts, Kun Zhang, Weiqian David Hong

Tropical Disease Biology

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

Abstract

A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus strains. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative showed good potency against all four strains of Staphylococcus (MIC = 1.25 - 5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase structure to rationalize the observed antibacterial activity. Therefore, this series of GA derivatives have strong potential for the development of a new type of triterpenoid antibacterial agent.

Original language	English
Article number	104692
Journal	Bioorganic Chemistry
Volume	109
Early online date	3 Feb 2021
DOIs	https://doi.org/10.1016/j.bioorg.2021.104692
Publication status	Published - 1 Apr 2021

Keywords

18β-glycyrrhetinic acid
Antibacterial
Gram-positive bacteria
Natural product derivatives
Pentacyclic triterpenes

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10.1016/j.bioorg.2021.104692

AR Synthesis and Biological Evaluation oAccepted author manuscript, 1.84 MBLicence: CC BY-NC-ND

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Wu, P., Tu, B., Liang, J., Guo, S., Cao, N., Chen, S., Luo, Z., Li, J., Zheng, W., Tang, X., Li, D., Xu, X., Liu, W., Zheng, X., Sheng, Z., Roberts, A., Zhang, K., & Hong, W. D. (2021). Synthesis and Biological Evaluation of Pentacyclic Triterpenoid Derivatives as Potential Novel Antibacterial Agents. Bioorganic Chemistry, 109, Article 104692. https://doi.org/10.1016/j.bioorg.2021.104692

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title = "Synthesis and Biological Evaluation of Pentacyclic Triterpenoid Derivatives as Potential Novel Antibacterial Agents",

abstract = "A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus strains. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative showed good potency against all four strains of Staphylococcus (MIC = 1.25 - 5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase structure to rationalize the observed antibacterial activity. Therefore, this series of GA derivatives have strong potential for the development of a new type of triterpenoid antibacterial agent.",

keywords = "18β-glycyrrhetinic acid, Antibacterial, Gram-positive bacteria, Natural product derivatives, Pentacyclic triterpenes",

author = "Panpan Wu and Borong Tu and Jinfeng Liang and Shengzhu Guo and Nana Cao and Silin Chen and Zhujun Luo and Jiahao Li and Wende Zheng and Xiaowen Tang and Dongli Li and Xuetao Xu and Wenfeng Liu and Xi Zheng and Zhaojun Sheng and Adam Roberts and Kun Zhang and Hong, \{Weiqian David\}",

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doi = "10.1016/j.bioorg.2021.104692",

language = "English",

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T1 - Synthesis and Biological Evaluation of Pentacyclic Triterpenoid Derivatives as Potential Novel Antibacterial Agents

AU - Wu, Panpan

AU - Tu, Borong

AU - Liang, Jinfeng

AU - Guo, Shengzhu

AU - Cao, Nana

AU - Chen, Silin

AU - Luo, Zhujun

AU - Li, Jiahao

AU - Zheng, Wende

AU - Tang, Xiaowen

AU - Li, Dongli

AU - Xu, Xuetao

AU - Liu, Wenfeng

AU - Zheng, Xi

AU - Sheng, Zhaojun

AU - Roberts, Adam

AU - Zhang, Kun

AU - Hong, Weiqian David

PY - 2021/4/1

Y1 - 2021/4/1

N2 - A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus strains. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative showed good potency against all four strains of Staphylococcus (MIC = 1.25 - 5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase structure to rationalize the observed antibacterial activity. Therefore, this series of GA derivatives have strong potential for the development of a new type of triterpenoid antibacterial agent.

AB - A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus strains. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative showed good potency against all four strains of Staphylococcus (MIC = 1.25 - 5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase structure to rationalize the observed antibacterial activity. Therefore, this series of GA derivatives have strong potential for the development of a new type of triterpenoid antibacterial agent.

KW - 18β-glycyrrhetinic acid

KW - Antibacterial

KW - Gram-positive bacteria

KW - Natural product derivatives

KW - Pentacyclic triterpenes

U2 - 10.1016/j.bioorg.2021.104692

DO - 10.1016/j.bioorg.2021.104692

M3 - Article

SN - 0045-2068

VL - 109

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 104692

ER -

Synthesis and Biological Evaluation of Pentacyclic Triterpenoid Derivatives as Potential Novel Antibacterial Agents

Abstract

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