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Structure-activity relationships of pyrazole-4-carbodithioates as antibacterials against methicillin–resistant Staphylococcus aureus

Journal Article


Abstract


  • Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in residential care facilities. New agents against MRSA are needed to combat rising resistance to current antibiotics. We recently reported 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) as a new bacteriostatic agent against MRSA that appears to act via a novel mechanism. Here, twenty nine analogs of HMPC were synthesized, their anti-MRSA structure-activity relationships evaluated and selectivity versus human HKC-8 cells determined. Minimum inhibitory concentrations (MIC) ranged from 0.5 to 64 μg/mL and up to 16-fold selectivity was achieved. The 4-carbodithioate function was found to be essential for activity but non-specific reactivity was ruled out as a contributor to antibacterial action. The study supports further work aimed at elucidating the molecular targets of this interesting new class of anti-MRSA agents.

Publication Date


  • 2018

Citation


  • Majed, H., Johnston, T., Kelso, C., Monachino, E., Jergic, S., Dixon, N. E., Mylonakis, E. & Kelso, M. J. (2018). Structure-activity relationships of pyrazole-4-carbodithioates as antibacterials against methicillin–resistant Staphylococcus aureus. Bioorganic and Medicinal Chemistry Letters, Online First 1-3.

Scopus Eid


  • 2-s2.0-85054478297

Number Of Pages


  • 2

Start Page


  • 1

End Page


  • 3

Volume


  • Online First

Place Of Publication


  • United Kingdom

Abstract


  • Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in residential care facilities. New agents against MRSA are needed to combat rising resistance to current antibiotics. We recently reported 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) as a new bacteriostatic agent against MRSA that appears to act via a novel mechanism. Here, twenty nine analogs of HMPC were synthesized, their anti-MRSA structure-activity relationships evaluated and selectivity versus human HKC-8 cells determined. Minimum inhibitory concentrations (MIC) ranged from 0.5 to 64 μg/mL and up to 16-fold selectivity was achieved. The 4-carbodithioate function was found to be essential for activity but non-specific reactivity was ruled out as a contributor to antibacterial action. The study supports further work aimed at elucidating the molecular targets of this interesting new class of anti-MRSA agents.

Publication Date


  • 2018

Citation


  • Majed, H., Johnston, T., Kelso, C., Monachino, E., Jergic, S., Dixon, N. E., Mylonakis, E. & Kelso, M. J. (2018). Structure-activity relationships of pyrazole-4-carbodithioates as antibacterials against methicillin–resistant Staphylococcus aureus. Bioorganic and Medicinal Chemistry Letters, Online First 1-3.

Scopus Eid


  • 2-s2.0-85054478297

Number Of Pages


  • 2

Start Page


  • 1

End Page


  • 3

Volume


  • Online First

Place Of Publication


  • United Kingdom