Promiscuous enzymatic synthesis of (S)-ibuprofen amides and assessment of their geroprotective and gastroprotective activities in Drosophila melanogaster

This study focuses on the optimization of the biocatalytic amidation of (S)-Ibuprofen [IBU], with primary amines under promiscuous enzymatic conditions. The use of drying agent as magnesium sulfate and Montmorillonite K10 instead of molecular sieves 4 Å, improved significantly the amidation rates, achieving yields of up to 90 %. The reaction was efficiently promoted by the Novozym®435 and enabled the synthesis of three (S)-Ibuprofen amide derivatives: (S)-2-(4-isobutylphenyl)-N-phenyl propanamide (2), (S)-2-(4-isobutylphenyl)-N-(4-(trifluoromethyl) phenyl) propanamide (3) and (S)-N-benzyl-2-(4-iso-butylphenyl) propanamide (4). In order to select the most suitable prodrug candidate, the synthesized amides were evaluated for predicted toxicity risks, drug-like properties and bioactivity scores using the online tools OSIRIS property explorer and Molinspiration. The compound (S)-4 [BZA] appeared to be the most promising and was selected to evaluate its geroprotective and gastroprotective activity using Drosophila melanogaster as a powerful model for drug discovery and screening. The in vivo results indicate that this amide prodrug enhances the geroprotective potency by increasing female’s survival, male’s locomotors reactivity and female’s fecundity, as compared to its parent drugs. A significant reduction in the gastric side effects associated with (S)-ibuprofen was also observed after the amidation process.