Synthesis of amino juglone derivatives with adjuvant activity against clinical isolated methicillin-resistant staphylococcus aureus strains

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 (CeCl₃·7H₂O) 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.

Adjuvant activity; Aminojuglone; Antibacterial activity; Structure elucidation; Synergistic effect.