Quinolones and their N-oxides as inhibitors of mitochondrial complexes I and III.
4(1H)-quinolones (2-alkyl- (1), 2-alkyl-3-methyl- (2), 2-methyl-3-alkyl- (3), 1-hydroxy-2-methyl-3-alkyl- (4) and 1-hydroxy-2-alkyl- (5)) with n-alkyl side chains varying from C5 to C17 have been synthesized and tested for biological activity in mitochondrial complexes. Whereas all quinolones were efficient inhibitors of electron transport in the cytochrome b/c1-complex from either beef heart or Rhodospirillum rubrum, in complex I from beef heart quinolones 1 and 2 only were highly active. In a Quantitative Structure-Activity Relationship (QSAR) inhibitory activity in the cytochrome b/c1-complexes could be correlated to the physicochemical parameters lipophilicity pi and/or to STERIMOL L. Maximal inhibitory potency was achieved at a carbon chain length of 12-14 A. Oxidant-induced reduction of cytochrome b established that some quinolones are inhibitors of the Qp rather than the Qn site.
Reil
E
E
Lehrstuhl Biochemie der Pflanzen, Ruhr-Universität, Bochum, Germany.
Höfle
G
G
Draber
W
W
Oettmeier
W
W
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003573:Cytochrome b Group / Q000378:metabolism; D003575:Cytochromes c1 / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology; D008929:Mitochondria, Heart / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012247:Rhodospirillum rubrum / Q000201:enzymology; D013329:Structure-Activity Relationship
D003573:Cytochrome b Group; D004791:Enzyme Inhibitors; D015363:Quinolones; D003575:Cytochromes c1; D016660:NAD(P)H Dehydrogenase (Quinone); D014450:Electron Transport Complex III