Relationship between chemical structure and antibacterial activity in methylated isoxazolylnaphthoquinones

Relationship between chemical structure and antibacterial activity of six isoxazolylnaphthoquinones was studied against Staphylococcus aureus including a methicillin resistant strain. Two drugs were enolic compounds (Q(2)-Q(3)) and the others were their ketonic derivatives (Q(4)-Q(5)) and their bis-isozaxolylnaphthoquinone derivatives (Q(6)-Q(7))Bacteria were inhibited by the stimuli of superoxide anion (O-2) produced by the new agents. Q(2) generated more O-2 in S. aureus than the other compounds. Introduction of a second methyl group in C-3 of the isoxazol ring reduced the antibacterial activity and O-2 generation. A second aminoisoxazolyl function in C-2 of the naphthoquinone ring inhibited the biological activity. The log P-oct was deter-mined by HPLC to establish its relationship with the antibiotic potency. High correlation was found between log P-oct and log k'(w) for all these structurally related compounds. Q(2) was the most active antibacterial and showed higher protective capacity in mouse infected with S. aureus. A unified antistaphylococcal mechanism via oxyradicals generation is proposed.