Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties

Wenjie Xue; Xueping Zuo; Xueqi Zhao; Xiaomin Wang; Xiangyu Zhang; Jie Xia; Maosheng Cheng; Huali Yang

doi:10.1016/j.bioorg.2024.107314

Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties

Bioorg Chem. 2024 Apr 3:147:107314. doi: 10.1016/j.bioorg.2024.107314. Online ahead of print.

Authors

Wenjie Xue¹, Xueping Zuo², Xueqi Zhao³, Xiaomin Wang⁴, Xiangyu Zhang⁵, Jie Xia⁶, Maosheng Cheng⁷, Huali Yang⁸

Affiliations

¹ Department of Pharmacy, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: xwj3516214@163.com.
² School of Materials and Environment, Shanxi Jinzhong Institute of Technology, Jinzhong 030600, China.
³ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁴ Department of Pharmacy, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁵ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
⁶ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
⁷ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: mscheng@syphu.edu.cn.
⁸ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: yanghl@syphu.edu.cn.

PMID: 38581967
DOI: 10.1016/j.bioorg.2024.107314

Abstract

The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC₅₀ values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.

Keywords: Antibacterial agent; Antibiotic resistance; Bioisosteric replacement; DNA Gyrase inhibitors; Molecular modeling.