Trifluoromethanesulfonamide anthelmintics. Protonophoric uncouplers of oxidative phosphorylation.
A series of trifluoromethanesulfonamides (TFMS) was synthesized and tested for uncoupling activity in rat liver mitochondria. With succinate as the mitochondrial substrate, and the respiratory control index (RCI) as an indicator of their uncoupling ability, we found that all of the TFMS tested were uncouplers of oxidative phosphorylation; the effective concentration (RCI I50) ranged from less than 1 microM to greater than 1000 microM. Correlation techniques were used to assess the strength of the relationship between the ability of a TFMS to uncouple oxidative phosphorylation and its ability to lower the electrical resistance of planar bimolecular lipid membranes. There was a highly significant (P < 0.001) positive linear relationship (r = 0.97) between the ability of a TFMS to uncouple oxidative phosphorylation and its ability to lower electrical resistance. These findings are consistent with the view that the TFMS are lipophilic protonophoric uncouplers of mitochondrial oxidative phosphorylation. Quantitative structure-activity relationship studies using experiment and semiempirical molecular orbital theory revealed that the hydrophobicity of a TFMS and its molecular dipole moment were the principal determinants of mitochondrial uncoupling activity within the pKa range examined.
Department of Biology, Indiana University-Purdue University, Indianapolis 46202.
R O
RO
McCracken
A W
AW
Carr
W H
WH
Stillwell
K B
KB
Lipkowitz
R
R
Boisvenue
G O
GO
O'Doherty
D I
DI
Wickiser
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D005617:Chlorofluorocarbons, Methane / Q000494:pharmacology*; D017097:Electric Impedance; D008566:Membranes / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D011522:Protons; D051381:Rats; D012756:Sheep; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology*
D000871:Anthelmintics; D005617:Chlorofluorocarbons, Methane; D011522:Protons; D013449:Sulfonamides; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone