2. Academic Validation
  3. Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity

Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity

  • Bioorg Chem. 2020 Oct;103:104176. doi: 10.1016/j.bioorg.2020.104176.
Runzhe Song 1,  Yue Wang 1,  Minghui Wang 2,  Ruixuan Gao 2,  Teng Yang 3,  Song Yang 4,  Cai-Guang Yang 5,  Yongsheng Jin 6,  Siyuan Zou 1,  Jianfeng Cai 7,  Renhua Fan 8,  Qiuqin He 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China.
  • 2 Department of Chemistry, University of South Florida, Tampa, FL 33620, United States.
  • 3 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, Guiyang 550025, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, 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, Guiyang 550025, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 School of Pharmacy, The Second Military Medical University, Shanghai 200433, China.
  • 7 Department of Chemistry, University of South Florida, Tampa, FL 33620, United States. Electronic address: [email protected].
  • 8 Department of Chemistry, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China. Electronic address: [email protected].
  • 9 Department of Chemistry, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China. Electronic address: [email protected].
PMID: 32891858 DOI: 10.1016/j.bioorg.2020.104176
Abstract

Despite the fact that the introduction of a fluorine atom at the C-6 position has resulted in the evolution of fluoroquinolones, fluoroquinolone-induced cardiac toxicity has drawn considerable attention. In this context, desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group were designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38 and 1.5 μg/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentrations against a panel of MRSA strains including vancomycin-intermediate strains, levofloxacin-resistant isolates, and linezolid-resistant isolates, etc. As expected, it also displayed highly selective toxicity toward Bacterial cells and low hERG inhibition. Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. The docking study revealed that two hydrogen bonds were formed between the C-7 substituent and the surrounding DNA bases, which might contribute to overcome resistance by reducing the dependence on the magnesium-water bridge interactions with Topoisomerase IV. These results indicate a promising strategy for developing new Antibiotic quinolones to combat multidrug resistance and cardiotoxicity.

Keywords

Aminopyrimidine; Anti-MRSA; Desfluoroquinolone; Hybrids; hERG activity.

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