Discovery of benzhydrol-oxaborole derivatives as Streptococcus pneumoniae leucyl-tRNA synthetase inhibitors

Guiyun Hao; Hao Li; Fei Yang; Duoling Dong; Zezhong Li; Yingying Ding; Wei Pan; Enduo Wang; Rujuan Liu; Huchen Zhou

doi:10.1016/j.bmc.2020.115871

Discovery of benzhydrol-oxaborole derivatives as Streptococcus pneumoniae leucyl-tRNA synthetase inhibitors

Bioorg Med Chem. 2021 Jan 1:29:115871. doi: 10.1016/j.bmc.2020.115871. Epub 2020 Nov 13.

Authors

Guiyun Hao¹, Hao Li², Fei Yang¹, Duoling Dong¹, Zezhong Li¹, Yingying Ding³, Wei Pan³, Enduo Wang⁴, Rujuan Liu⁵, Huchen Zhou⁶

Affiliations

¹ State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.
² State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, People's Republic of China.
³ Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, People's Republic of China.
⁴ State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, People's Republic of China. Electronic address: edwang@sibcb.ac.cn.
⁵ School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, People's Republic of China. Electronic address: liurj@shanghaitech.edu.cn.
⁶ State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China. Electronic address: hczhou@sjtu.edu.cn.

PMID: 33221064
DOI: 10.1016/j.bmc.2020.115871

Abstract

Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l-leucine to tRNA^Leu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of SpLeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure-activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS.

Keywords: Anti-pneumonia; Benzhydrol-Oxaborole; S. pneumonia LeuRS (SpLeuRS); Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Benzhydryl Compounds / chemistry
Benzhydryl Compounds / pharmacology*
Boron Compounds / chemistry
Boron Compounds / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Leucine-tRNA Ligase
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Streptococcus pneumoniae / drug effects*
Streptococcus pneumoniae / enzymology
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Benzhydryl Compounds
Boron Compounds
Enzyme Inhibitors
Leucine-tRNA Ligase
benzohydrol