Physicochemical properties of acedoben and its trifluoroacetamido derivative

• Published in: Results in Chemistry 2023-12, Vol.6, p.101075, Article 101075
• Main Authors: Boldon, Joshua A., Shell, Thomas A.
• Format: Article
• Language: English
• Subjects: 4-Acetamidobenzoic acid; Acedoben; Fluorine derivative; N-Acetyl-Paba
• ISSN: 2211-7156; 2211-7156
• DOI: 10.1016/j.rechem.2023.101075

[Display omitted] Acedoben (4-acetamidobenzoic acid, AcPABA) is a component of the antiviral drug inosine pranobex. The introduction of fluorine has been proven to change the physicochemical properties of molecules. For example, the trifluoromethyl group generally improves the lipophilicity of molecules, which is an important physical property for the bioavailability of drugs. A trifluoroacetamido derivative of acedoben (3F-AcPABA) was synthesized and its physicochemical properties were compared to AcPABA. The acidity of AcPABA and 3F-AcPABA is equivalent as demonstrated by the observed pKa values of their carboxylic acid functional groups. However, octanol–water partition coefficients determined at pH 2.0 (Kow) show that 3F-AcPABA is over seven times more lipophilic than AcPABA. In addition, distribution coefficients (logD) measured using an octanol–water partition experiment at pH 7.4 demonstrate that AcPABA has a greater than four-fold increased distribution in the aqueous phase relative to 3F-AcPABA. These results suggest that 3F-AcPABA would have an improved ability to passively cross cellular membranes at physiologically relevant pH environments in comparison to AcPABA based on the increased lipophilicity of 3F-AcPABA relative to AcPABA. These results indicate that 3F-AcPABA would likely have improved bioavailability relative to AcPABA.