Capsaicin derivatives with nitrothiophene substituents: Design, synthesis and antibacterial activity against multidrug-resistant S. aureus

Zhi-Cheng Wang; Bingyan Wei; Fang-Ning Pei; Teng Yang; Jie Tang; Song Yang; Li-Fang Yu; Cai-Guang Yang; Fan Yang

doi:10.1016/j.ejmech.2020.112352

Capsaicin derivatives with nitrothiophene substituents: Design, synthesis and antibacterial activity against multidrug-resistant S. aureus

Eur J Med Chem. 2020 Jul 15:198:112352. doi: 10.1016/j.ejmech.2020.112352. Epub 2020 Apr 28.

Authors

Zhi-Cheng Wang¹, Bingyan Wei², Fang-Ning Pei¹, Teng Yang³, Jie Tang¹, Song Yang⁴, Li-Fang Yu¹, Cai-Guang Yang⁵, Fan Yang⁶

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, SCME, East China Normal University, Shanghai, 200062, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of the Chinese Academy of Sciences, Beijing, 100049, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals, Guizhou University, 2708 South Huaxi Road, Guiyang, Guizhou, 550025, China.
⁴ State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals, Guizhou University, 2708 South Huaxi Road, Guiyang, Guizhou, 550025, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of the Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
⁶ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, SCME, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].

PMID: 32387838
DOI: 10.1016/j.ejmech.2020.112352

Abstract

To address the emergency caused by multi-drug resistant Staphylococcus aureus, a series of novel capsaicin derivatives with nitrothiophene substituents have been designed and evaluated for the antibacterial activities against S. aureus Newman and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The structure-activity relationship was further revealed. Compound 13c, 13f, and 13g were highly active against staphylococcal growth, with minimal inhibition concentration (MIC) values of 0.39-1.56 μg/mL. The oxadiazole-derived compound 21, a bioisostere of ester 13f, is the most potent candidate for anti-growth of five multidrug-resistant S. aureus strains with MICs of 0.20-0.78 μg/mL, which is more active compared with vancomycin in vitro. Notably, these anti-staphylococcal compounds are much less cytotoxic to the normal kidney epithelial cell line (HK293T).

Keywords: Antibacterial agent; Capsaicin; Multidrug-resistant S. aureus; Nitrothiophene.

MeSH terms

Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / pharmacology
Capsaicin / chemical synthesis*
Capsaicin / pharmacology
Cell Survival / drug effects
Drug Design
Drug Resistance, Multiple
HEK293 Cells
Humans
Methicillin-Resistant Staphylococcus aureus / drug effects*
Microbial Sensitivity Tests
Oxadiazoles / chemistry
Staphylococcal Infections / drug therapy*
Structure-Activity Relationship
Thiophenes / chemistry*
Vancomycin / pharmacology

Substances

Anti-Bacterial Agents
Oxadiazoles
Thiophenes
Vancomycin
Capsaicin