ABSTRACT
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 C(5) to C(17) have been synthesized and tested for biological activity in photosystem II and the cytochrome b(6)/f-complex. In photosystem II, quinolones 1 and 2 showed only moderate activity, whereas 3<5<4 (increasing activity) were potent inhibitors. Displacement experiments with [(14)C]atrazine indicated that the quinolones share an identical binding site with other photosystem II commercial herbicides. In the cytochrome b(6)/f-complex, only 3<4 showed enhanced activity. Maximal inhibitory potency was achieved at a carbon chain length of 12-14 A. Further increase of the chain length decreased activity. In a quantitative structure-activity relationship inhibitory activity in photosystem II and the cytochrome b(6)/f-complex could be correlated to the physicochemical parameters lipophilicity pi and/or to STERIMOL L.
Subject(s)
Cytochrome b Group/chemistry , Photosynthetic Reaction Center Complex Proteins/antagonists & inhibitors , Quinolones/pharmacology , Binding Sites , Cytochrome b6f Complex , Electron Transport/drug effects , Molecular Structure , Photosystem II Protein Complex , Quinolones/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Electron Transport Complex III/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , NAD(P)H Dehydrogenase (Quinone)/antagonists & inhibitors , Quinolones/pharmacology , Animals , Binding Sites , Cattle , Cytochrome b Group/metabolism , Cytochromes c1/metabolism , Electron Transport/drug effects , Electron Transport Complex III/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , In Vitro Techniques , Kinetics , Mitochondria/enzymology , Mitochondria, Heart/enzymology , NAD(P)H Dehydrogenase (Quinone)/chemistry , Quinolones/chemical synthesis , Quinolones/chemistry , Rhodospirillum rubrum/enzymology , Structure-Activity RelationshipABSTRACT
The folding through the thylakoid membrane of the D-1 herbicide binding polypeptide and of the homologous D-2 subunit of photosystem II is predicted from comparison of amino acid sequences and hydropathy index plots with the folding of the subunits L and M of a bacterial photosystem. As the functional amino acids involved in Q and Fe binding in the bacterial photosystem of R. viridis, as indicated by the X-ray structure, are conserved in the homologous D-1 and D-2 subunits of photosystem II, a detailed topology of the binding niche of QB and of herbicides on photosystem II is proposed. The model is supported by the observed amino acid changes in herbicide tolerant plants and algae. These changes are all in the binding domain on the matrix side of the D-1 polypeptide, and turn out to be of functional significance in the QB binding.New inhibitors of QB function are described. Their chemical structure, i.e. pyridones, quinolones, chromones and benzodiones, contains the features of the phenolic type herbicides. Their essential elements, π-charges at particular atoms, QSAR and steric requirements for optimal inhibitory potency are discussed and compared with the "classical" herbicides of the urea/triazine type.
ABSTRACT
Clotrimazole and triadimefon are known as potent inhibitors of ergosterol synthesis in pathogenic yeast and fungi, respectively. As their mode of action generally the inhibition of sterol desmethylation reactions is accepted. We report about a second effect, a "feed-back" inhibition of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA-reductase by accumulation of ergosterol precursors. Addition of lanosterol to intact cells leads to an inhibition of HMG-CoA-reductase as well, but not to fungistatic effects. From the reported data the influences of clotrimazole and triadimefon have to be considered as an inhibition of desmethylation reactions involved in ergosterol synthesis of yeast and fungi with a concomitant decreased production of mevalonate.
