Design, Synthesis, and Biological Activity of Thioguanine-Modified Pleuromutilin Derivatives

Can Yong; Jianglin Yu; Chunxia Wu; Xiujuan Zhang; Yun Li; Chuan Xie; Xiaolong He; Dongfang Liu; Zhouyu Wang; Peng Lai; Yuanyuan Zhang

doi:10.1021/acsmedchemlett.3c00004

Design, Synthesis, and Biological Activity of Thioguanine-Modified Pleuromutilin Derivatives

ACS Med Chem Lett. 2023 May 10;14(6):737-745. doi: 10.1021/acsmedchemlett.3c00004. eCollection 2023 Jun 8.

Authors

Can Yong¹, Jianglin Yu¹, Chunxia Wu¹, Xiujuan Zhang², Yun Li¹, Chuan Xie¹, Xiaolong He^{2

3}, Dongfang Liu^{1

3}, Zhouyu Wang^{1

3}, Peng Lai², Yuanyuan Zhang^{1

3}

Affiliations

¹ Department of Chemistry, School of Science, Xihua University, Chengdu 610039, China.
² Department of Pharmaceutical Engineering, School of Food and Bioengineering, Xihua University, Chengdu 610039, China.
³ Asymmetric Synthesis and Chiral Technology Key Laboratory of Sichuan Province, Chengdu 610041, China.

Abstract

Antibiotic overuse has caused the increasingly serious problem of bacterial drug resistance, with numerous marketed antibiotics exhibiting significantly reduced activity against drug-resistant bacteria. Therefore, there is urgent demand for the development of novel antibiotics. Pleuromutilin is a tricyclic diterpene exhibiting antibacterial activity against Gram-positive bacteria and is currently considered the most promising natural antibiotic. In this study, novel pleuromutilin derivatives were designed and synthesized by introducing thioguanine units, and their antibacterial activities against drug-resistant strains were evaluated in vitro and in vivo. Compound 6j was observed to have a rapid bactericidal effect, low cytotoxicity, and potent antibacterial activity. The in vitro results suggest that 6j has a significant therapeutic effect on local infections, and its activity is equal to that of retapamulin, an anti-Staphylococcus aureus pleuromutilin derivative.