Synthesis of amino juglone derivatives with adjuvant activity against clinical isolated methicillin-resistant staphylococcus aureus strains
Résumé
A C T 1,4-naphthoquinones hydroxyderivatives belong to an important class of natural products and have been known as a favored scaffold in medicinal chemistry due to their multiple biological properties. Juglone is one of the most important 1,4-naphthoquinone extracted from juglandaceae family showing a good antibacterial activity. In this study, we report the synthesis of aminojuglone derivatives through Michael addition reaction using Cerium (III) chloride heptahydrate (CeCl 3 ⋅7H 2 O) as catalyst. The synthesized aminojuglone derivatives were evaluated for their antibacterial properties against sensitive, clinical resistant Gram-positive and Gram-negative bacterial strains. Compound 3c showed a good antibacterial activity similar to cloxacillin (2 µg/mL) against the clinically resistant S.aureus. The antibiotic adjuvant activity of compounds was evaluated in combination with three clinically use antibiotics. The combination of compounds 3a, 3b, 3e, 3 h-3 l, 3n and 3o with cloxacillin showed remarkable adjuvant activity against clinically resistant S. aureus (66-fold potentiation of cloxacillin activity). 3e is the only compound consistent with the concept of antibiotic adjuvant, presenting insufficient antibacterial activity (MIC > 128 µg/mL) and potentiate the activity of cloxacillin (66-fold) with synergistic effect. A structural characterization of 3e was carried out for the first time using X-ray diffraction technic. Moreover, compound 3e did not show a cytotoxic activity on sheep red blood cells.
Mots clés
- E. coli
- FICI
- Fractional Inhibitory Concentration Index
- RBC
- Aminojuglone Structure elucidation Antibacterial activity Adjuvant activity Synergistic effect AB
- Antibiotic WHO
- World Health organization E. coli
- Escherichia coli K.pneumoniae
- Klebsiella pneumoniae P. aeruginosa
- Pseudomonas aeruginosa SASM
- methicillin sensitive S. aureus NSARM-1
- methicillin clinical resistant S. aureus NEC-R2
- clinical resistant E. coli to cefotaxime NPA-R1
- clinical resistant P. aeruginosa to imipenem NKP-R1
- clinical resistant K. pneumoniae to cefotaxime MIC
- Minimal Inhibitory Concentration CFT
- Cefotaxime VCM
- Vancomycin CXL
- Cloxacilline FICI
- Fractional Inhibitory Concentration Index RBC
- red blood cells
- Antibiotic
- WHO
- World Health organization
- clinical resistant E. coli to cefotaxime
- Escherichia coli
- K.pneumoniae
- Klebsiella pneumoniae
- P. aeruginosa
- Pseudomonas aeruginosa
- SASM
- methicillin sensitive S. aureus
- NSARM-1
- methicillin clinical resistant S. aureus
- NEC-R2
- Cloxacilline
- NPA-R1
- clinical resistant P. aeruginosa to imipenem
- NKP-R1
- clinical resistant K. pneumoniae to cefotaxime
- MIC
- Minimal Inhibitory Concentration
- CFT
- Cefotaxime
- VCM
- Vancomycin
- CXL