The synthesis and SAR study of phenylalanine-derived (Z)-5-arylmethylidene rhodanines as anti-methicillin-resistant Staphylococcus aureus (MRSA) compounds

Bioorg Med Chem Lett. 2013 Oct 15;23(20):5523-7. doi: 10.1016/j.bmcl.2013.08.059. Epub 2013 Aug 20.

Abstract

A focused library of rhodanine compounds containing novel substituents at the C5-position was synthesized and tested in vitro against a panel of clinically relevant MRSA strains. The present SAR study was based on our lead compound 1 (MIC=1.95 μg/mL), with a focus on identifying optimal C5-arylidene substituents. In order to obtain this objective, we condensed several unique aromatic aldehydes with phenylalanine-derived rhodanine intermediates to obtain C5-substituted target rhodanine compounds for evaluation as anti-MRSA compounds. These efforts produced three compounds with significant efficacy: 23, 32 and 44, with MIC values ranging from 0.98 to 1.95 μg/mL against all tested MRSA strains as compared to the reference antibiotics penicillin G (MIC=15.60-250.0 μg/mL) and ciprofloxacin (MIC=7.80-62.50 μg/mL) and comparable to that of vancomycin (MIC=0.48 μg/mL). In addition, compounds 24, 28, 37, 41, 46 and 48 (MIC=1.95-3.90 μg/mL) were efficacious against all MRSA strains. The majority of the synthesized compounds had bactericidal activity at concentrations only two to fourfold higher than their MIC. Overall, the results suggest that compounds 23, 32 and 44 may be of potential use in the treatment of MRSA infections.

Keywords: Knoevenagel condensation; MRSA; Rhodanine; Serum; Stereochemistry; Ullmann condensation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Microbial Sensitivity Tests
  • Phenylalanine / chemistry*
  • Rhodanine / chemical synthesis
  • Rhodanine / chemistry*
  • Rhodanine / pharmacology
  • Structure-Activity Relationship
  • Vancomycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Phenylalanine
  • Vancomycin
  • Rhodanine