Substituted α‐(phenylhydrazono)phenylacetonitrile derivatives. Part 1: A new class of uncoupler of oxidative phosphorylation

Abstract

Substituted alpha-(phenylhydrazono)phenylacetonitrile derivatives have been discovered which constitute a series of potent uncouplers of oxidative phosphorylation. Systematic variation of substituents on both benzene rings has clearly demonstrated the importance of steric congestion around the ionisation site and delocalisation of negative charge in the anionic form. Replacement of the cyano group by other electron-withdrawing groups leads to a dramatic decrease in uncoupling activity. The sub-nanomolar levels of uncoupling activity found in certain members indicate that these compounds are the most potent uncouplers yet reported.

Substituted α‐(phenylhydrazono)phenylacetonitrile derivatives. Part 2: synthesis and biological activity of pro‐pesticides

“…The preparation of compound 1 has already been described 1, 2. Synthesis of N ‐(substituted)‐alkyl and ‐acyl derivatives 2 was straightforward and achieved using standard procedures10 (Fig.…”

“…Mitochondria preparation from flight muscles of adult blowflies, Protophormia terraenovae (Robineau‐Desvoidy), and measurement of respiration employing a Clark oxygen electrode were accomplished as described in Part 1 1. Mitochondria were incubated for 13 min with the respective compound before addition of FCCP (a control showed no detectable oxygen consumption within this time).…”

“…We have previously reported the synthesis of α‐(2,6‐dichloro‐4‐trifluoromethylphenylhydrazono)‐4‐nitrophenylacetonitrile (Fig. 1, 1 ) and related substituted α‐(phenylhydrazono)phenylacetonitrile derivatives 1, 2. These compounds represent a new class of very potent uncouplers of oxidative phosphorylation.…”

The importance of trifluoromethyl pyridines in crop protection

“…These hydrazono‐phenyl‐acetonitrile derivatives (Fig. ) are the most potent uncouplers of oxidative phosphorylation reported to date . Two properties of a molecule have been reported to be important for this mode of action, lipophilicity and p K a , because such molecules need to cross mitochondrial membranes to accept and donate a proton.…”

“…Most potent uncouplers have been reported to have a lipophilicity, depicted as LogP, in the range 6–6.5, and p K a of ∼ 7.5. A molecular matched pair analysis showing predicted LogP values, calculated p K a values, and measured uncoupling of oxidative phosphorylation activity expressed as EC 50 is shown in Fig. .…”