Synthesis, molecular docking, and antiepileptic activity of novel phthalimide derivatives bearing amino acid conjugated anilines

A series of N-aryl-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanamides derivatives were synthesized in two steps. Phthalic anhydride and phenylalanine are first reacted under microwave radiation to form 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid, which finally took part in an amidation reaction with different anilines. The final products were characterized by infrared, proton nuclear magnetic resonance (1</sup>H NMR) and mass spectroscopy techniques. The antiepileptic activity of the synthesized compounds at a fixed dose of 10 mg/kg was evaluated by pentylenetetrazole at 70 mg/kg induced seizure threshold method in male mice (n = 5) and compared with aqueous DMSO (10 %, v/v; as negative control) and thalidomide (70 mg/kg; as positive control). The results indicated that compounds 5c, 5e, </strong>and 5f</strong> as well as thalidomide significantly have higher latency time than what observed with aqueous DMSO (P</em> < 0.05). The seizure latency threshold for 5e</strong> and 5f</strong> were statistically similar to the results of thalidomide but compound 5c</strong> showed significantly higher latency time than thalidomide. While, the electron-deficient benzene ring (5a</strong> and 5b</strong>) has demonstrated the lowest activity but compound 5e</strong>, which is the most electron rich product among tested compounds, showed good antiepileptic activity. Molecular docking was performed in order to understand how the synthetized compounds, interact with gamma-aminobutyric acid (GABA)A</sub> receptor. Docking results were in good harmony with experimental data and indicated that lowest binding energy belongs to compound 5c</strong>, which has strongest interactions with the active site of GABAA</sub> receptor. Compound 5c</strong> could be used for further investigation.