Design, synthesis and antibacterial evaluation of 2,4-disubstituted-6-thiophenyl-pyrimidines

Zhiyuan Fang; Sichao Zheng; Kin-Fai Chan; Wenchang Yuan; Qi Guo; Wenyu Wu; Hoi-Kui Lui; Yujing Lu; Yun-Chung Leung; Tak-Hang Chan; Kwok-Yin Wong; Ning Sun

doi:10.1016/j.ejmech.2018.10.039

Design, synthesis and antibacterial evaluation of 2,4-disubstituted-6-thiophenyl-pyrimidines

Eur J Med Chem. 2019 Jan 1:161:141-153. doi: 10.1016/j.ejmech.2018.10.039. Epub 2018 Oct 17.

Authors

Zhiyuan Fang¹, Sichao Zheng¹, Kin-Fai Chan², Wenchang Yuan¹, Qi Guo³, Wenyu Wu³, Hoi-Kui Lui⁴, Yujing Lu⁵, Yun-Chung Leung⁴, Tak-Hang Chan⁶, Kwok-Yin Wong⁷, Ning Sun⁸

Affiliations

¹ The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, PR China.
² State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China. Electronic address: kf.chan@polyu.edu.hk.
³ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, PR China.
⁴ State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
⁵ Institute of Natural Medicine and Green Chemistry, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China.
⁶ State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China; Department of Chemistry, McGill University, Montreal, Quebec, H3A 2K6, Canada.
⁷ State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China. Electronic address: kwok-yin.wong@polyu.edu.hk.
⁸ The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, PR China; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China. Electronic address: ning.sun@connect.polyu.hk.

PMID: 30347327
DOI: 10.1016/j.ejmech.2018.10.039

Abstract

The increasing incidences of multidrug resistant bacterial infections urge the development of novel antibacterial having a new mechanism of action. The small molecule-based inhibitors targeting at the cell division protein FtsZ has been recognized as a promising approach to search for new antibacterial with high potency. In the present study, a series of novel 2,4-disubstituted-6-thiophenyl-pyrimidine derivatives were synthesized and their antibacterial activities against clinically related pathogens were investigated. The compounds show strong antibacterial activities against MRSA and VREs. The antibacterial activity of compound Bb2 against MRSA and VREs (MIC values: 2 μg/mL) is stronger than that of methicillin and vancomycin. From the in vitro and in vivo results, Bb2 was found to inhibit GTPase activity and FtsZ polymerization. The compound is able to inhibit bacterial cell division through interacting with GTP binding site of FtsZ and thus causing cell death. In addition, S. aureus was found to develop resistance to methicillin but not for Bb2, which was proved in our resistance generation experiments.

Keywords: 2,4-Disubstituted-6-thiophenyl-pyrimidines; Antibacterial activity; Bacterial resistance; FtsZ inhibition.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Methicillin-Resistant Staphylococcus aureus / drug effects*
Microbial Sensitivity Tests
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*
Vancomycin-Resistant Enterococci / drug effects*

Substances

Anti-Bacterial Agents
Pyrimidines
Thiophenes