QUINOLONES AND THEIR N-OXIDES AS INHIBITORS OF MITOCHONDRIAL COMPLEX-I AND COMPLEX-III

4(1H)-quinolones (2-alkyl- (1), 2-alkyl-3-methyl- (2), 2-methyl-3-alky l- (3), 1-hydroxy-2-methyl-3-alkyl- (4) and 1-hydroxy-2-alkyl- (5)) wi th n-alkyl side chains varying from C-5 to C-17 have been synthesized and tested for biological activity in mitochondrial complexes. Whereas all quinolones were efficient inhibitors of electron transport in the cytochrome b/c(1)-complex from either beef heart or Rhodospirillum ru brum, in complex I from beef heart quinolones 1 and 2 only were highly active. In a Quantitative Structure-Activity Relationship (QSAR) inhi bitory activity in the cytochrome b/c(1)-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 o f 12-14 Angstrom. Oxidant-induced reduction of cytochrome b establishe d that some quinolones are inhibitors of the Q(p) rather than the Q(n) site.