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

摘要

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 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, and 5f as well as thalidomide significantly have higher latency time than what observed with aqueous DMSO ( P 0.05). The seizure latency threshold for 5e and 5f were statistically similar to the results of thalidomide but compound 5c showed significantly higher latency time than thalidomide. While, the electron-deficient benzene ring ( 5a and 5b ) has demonstrated the lowest activity but compound 5e , 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 receptor. Docking results were in good harmony with experimental data and indicated that lowest binding energy belongs to compound 5c , which has strongest interactions with the active site of GABA A receptor. Compound 5c could be used for further investigation.