Physicochemical properties of N,N'-(1,4-phenylene)bis(2,2,2-trifluoroacetamide), the bis(trifluoromethyl) derivative of N,N′-diacetyl-p-phenylenediamine

Neuroinflammation is a significant factor in the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease. It has been previously reported that the cognitive defects of AD transgenic mice are improved by the antineuroinflammatory agent, N , N ′-diacetyl- p -phenylenediamine ( DAPPD ). Antineuroinflammatory drugs must effectively cross the blood brain barrier (BBB). There is a correlation between the ability of molecules to passively transit the BBB and their lipophilicity. The lipophilicity of molecules is often increased by substituting hydrogens with fluorines. The strong electron-withdrawing nature of fluorine changes the electron density distribution of the molecule, which alters physicochemical properties, such as acidity and lipophilicity. However, the size and the shape of the molecule is not significantly changed by the fluorine substitution because fluorine and hydrogen have similar atomic radii. Therefore, the bis(trifluoromethyl) derivative of DAPPD ( 6F-DAPPD ) was synthesized and its physicochemical properties were compared to those of DAPPD . Relative to DAPPD , 6F-DAPPD is significantly more acidic. The lipophilicity of 6F-DAPPD is 85-fold greater than that of DAPPD based on octanol-water partition experiments. This remarkable difference in lipophilicity suggests that in comparison to DAPPD , 6F-DAPPD would have increased bioavailability as well as enhanced ability to passively cross the BBB.