Structure-activity relationships of stemphones, potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus.
From a further purification study, four new stemphones D to G were isolated along with previously reported stemphones B and C from the culture broth of Aspergillus sp. FKI-2136. Twenty-one derivatives were semisynthetically prepared from stemphones C, E and G. Potentiation of imipenem activity against methicillin-resistant Staphylococcus aureus (MRSA) by all the stemphones including natural and semisynthetic ones was compared to study the structure-activity relationships. Derivatives with a free hydroxy or an O-acyl residue having a C2 to C5 carbon length at C-4 held the potentiating activity, but those with a longer acyl residue lost the activity. The presence of an oxo or a free hydroxy residue at C-10 is important for the potentiating activity because introduction of an alkyl or acyl residue at this position resulted in a loss of activity. Among them, stemphone E exhibited the most potent potentiation of imipenem activity against MRSA and the lowest cytotoxic activity against Jurkat cells.
Yamazaki
Hiroyuki
H
School of Pharmacy, Kitasato University, Tokyo, Japan.
Koyama
Nobuhiro
N
Omura
Satoshi
S
Tomoda
Hiroshi
H
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001230:Aspergillus / Q000378:metabolism; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D003470:Culture Media / Q000737:chemistry; D006801:Humans; D015378:Imipenem / Q000494:pharmacology*; D019169:Jurkat Cells; D016106:Methicillin Resistance; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D016227:Benzoquinones; D003470:Culture Media; C087469:stemphone; D015378:Imipenem