N-acyl derivatives of 4-phenoxyaniline as neuroprotective agents

Neuronal cell death is the main cause behind the progressive loss of brain function in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanisms such as oxidative stress, impaired calcium homeostasis, and disrupted mitochondrial integrity and function. In particular, mitochondrial fragmentation, mitochondrial membrane permeability, and the release of death-promoting factors into the cytosol have been revealed as the "point of no return" in programmed cell death in neurons. Recent studies revealed a pivotal role for the pro-apoptotic Bcl-2-family protein Bid in models of neuronal cell death, which confirmed Bid as a potential drug target. Herein, we present N-acyl-substituted derivatives of 4-phenoxyaniline that were screened for their potential to attenuate Bid-mediated neurotoxicity. These compounds provided significant protection against glutamate- and Bid-induced toxicity in cultured neurons. Substitution of the amino group in the 4-phenoxyaniline scaffold with 4-piperidine carboxylic acid and N-hydroxyethyl-4-piperidine carboxylic acid yielded compounds that displayed significant neuroprotective activity at concentrations as low as 1 μM. Furthermore, findings of a tBid-overexpression assay and real-time measurements of cell impedance support the hypothesis that these compounds indeed address the Bid protein.