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

Azar Asadollahi, Mehdi Asadi, Faezeh Sadat Hosseini, Zeinab Ekhtiari, Mahmood Biglar, Massoud Amanlou


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 (1H 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 GABAA receptor. Compound 5c could be used for further investigation.


Antiepileptic agent; Microwave synthesis; Molecular docking simulation; Phenylalanine; Phthalimide derivatives.

Full Text:



Simonato M. Epilepsy an update on disease mechanisms: the potential role of microRNAs. Front Neurol. 2018;9:176-182.

Kakooza A. Infections as a cause for seizures and epilepsy: an underestimated epidemic. J Neurol Sci. 2015;357:E458-E459.

Bosak M, Sowa-Staszczak A, Slowik A. Insulinoma mimicking psychogenic non-epileptic seizures in a patient with refractory epilepsy. Pol Arch Intern Med. 2019;129(7-8):545-546..

Sugawara T, Mazaki-–Miyazaki E, Ito M, Nagafuji H, Fukuma G, Mitsudome A, et al. Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures. Neurology. 2001;57(4): 703-705.

Melchert M, List A. The thalidomide saga. Int J Biochem Cell Biol. 2007;39(7-8):1489-1499.

Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, Tuckova L, Cukrowska B, Lodinova-Zadnikova R, et al. Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immuno Lett. 2004;93 (2-3):97-108.

Mercurio A, Adriani G, Catalano A, Carocci A, Rao L, Lentini G, et al. A mini-review on thalidomide: chemistry, mechanisms of action, therapeutic potential and anti-angiogenic properties in multiple myeloma. Curr Med Chem. 2017;24(25):2736-2744.

Camarasa MJ. Heterocyclic chemistry in drug discovery. Chem Med Chem. 2014;9(1):233-234.

Rahimzadeh G, Bahadorikhalili S, Kianmehr E, Mahdavi M. Ionic liquid-functionalized magnetic nanostructures as an efficient catalyst for the synthesis of 6H-chromeno[4,3-b]quinolin- 6-ones. Mole Divers. 2017;21(3):597-609.

Gali H, Prabhu KR, Karra SR, Katti KV. Facile ring-opening reactions of phthalimides as a new strategy to synthesize amide-functionalized phosphonates, primary phosphines, and bisphosphines. J Org Chem. 2000;65(3):676-680.

Wei WH, Fountain M, Magda D, Wang Z, Lecane P, Mesfin M, et al. Gadolinium texaphyrin–methotrexate conjugates. Towards improved cancer chemotherapeutic agents. Org Biomol Chem. 2005;3(18):3290-3296.

Li Y, Yang W. Microwave synthesis of zeolite membranes: A review. J Membrane Sci. 2008;316(1-2):3-17.

Oghbaei M, Mirzaee O. Microwave versus conventional sintering: A review of fundamentals, advantages and applications. J Alloy Compd. 2010;494(1-2):175-189.

Panda AB, Glaspell G, El-Shall MS. Microwave synthesis of highly aligned ultra narrow semiconductor rods and wires. J Am Chem Soc. 2006;128(9):2790-2791.

Kappe CO. High-speed combinatorial synthesis utilizing microwave irradiation. Curr Opin Chem Biol. 2002;6(3):314-320.

Wang XH, Qu KG, Xu BL, Ren JS, Qu XG. Microwave assisted one-step green synthesis of cell-permeable multicolor photoluminescent carbon dots without surface passivation reagents. J Mater Chem. 2011;21(8):2445-2450.

Kappe CO, Dallinger D, Murphree SS. Practical microwave synthesis for organic chemists. Strategies, Instruments, and Protocols. Germany, Weinheim: Wiley-VCH, 2009. pp. 1-9.

Ahuja P, Husain SAL, Siddiqui NA. Essential aminoacid incorporated GABA-phthalimide derivatives: synthesis and anticonvulsant evaluation. Med Chem Res. 2014;23(9):4085-4098.

Shendage DM, Fröhlich R, Haufe G. Highly efficient stereoconservative amidation and deamidation of α-amino acids. Org Lett. 2004;6(21):3675-3678.

Yu P, Hu J, Zhou TY, Wang P, Xu YH. Synthesis, insecticidal evaluation of novel 1, 3, 4-thiadiazole chrysanthemamide derivatives formed by an EDCI/HOBt condensation. J Chem Res. 2011;35(12):703-706.

Sheehan JC, Frank VS. A new synthetic route to peptides. J Am Chem Soc. 1949;71(5):1856-1861.

Essawy SA, El-Aleem, AHA, Donia SG, Metwally RN. Synthesis and reactions of phthalimido aliphatic acid azides. Pol J Chem. 1991;65(7-8):1243-1250.

Wei Q, Ma Y, Li L, Liu Q, Liu Z, Liu G. Synthesis of quaternary α-fluorinated α-amino acid derivatives via coordinating Cu(II) catalytic α-C(1sp3)-H direct fluorination. Org Lett. 2018;20(22):7100-7103.

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J Comput Chem. 2009;30(16):2785-2791.

Richter L, de Graaf C, Sieghart W, Varagic Z, Morzinger M, de Esch IJ, et al. Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands. Nat Chem Biol. 2012;8(5):455-464.

ChemAxon. MarvinSketch. Version 15.10.12 [software]. 2009 [cited: 2009 June 30]. Availale from: http://www. 531 product/msketch.html.

Mendelsohn LD. ChemDraw 8 ultra, windows and macintosh versions. J Chem Inf Comp. Sci. 2004;44(6):2225-2226.

Shirgahi Talari F, Bagherzadeh K, Golestanian S, Jarstfer M, Amanlou M. Potent human telomerase inhibitors: molecular dynamic simulations, multiple pharmacophore-based virtual screening, and biochemical assays. J Chem Inf Model. 2015;55(12):2596-2610.

Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes. Version 17.2 [software].2016. Available from: products/collaborative-science/biovia-discovery-studio.

The PyMOL Molecular Graphics System. Version 1.1evel, Schrödinger, LLC. Available from:

Palencia G, Calderon A, Sotelo J. Thalidomide inhibits pentylenetetrazole-induced seizures. J Neurol Sci. 2007;258(1-2):128-131.

Mercurio A, Sharples L, Corbo F, Franchini C, Vacca A, Catalano A, et al. Phthalimide derivative shows anti-angiogenic activity in a 3D microfluidic model and no teratogenicity in zebrafish embryos. Front Pharmacol. 2019;10:349-360.

Iman M, Fakhari S, Jahanpanah M, Naderi N, Davood A. Design and synthesis of 4-flurophthalimides as potential anticonvulsant agents. Iran J Pharm Res. 2018;17(3):896-905.

Chan LC, Cox BG. Kinetics of amide formation through carbodiimide/N-hydroxybenzotriazole (HOBt) couplings. J Org Chem. 2007;72(23): 8863-8869.

Kiminejad Malaie P, Asadi M, Hosseini FS, Biglar M, Amanlou M. Synthesis, in vivo and in silico studies of N-aryl-4-(1,3-dioxoisoindolin-2-yl)benzamides as an anticonvulsant agent. Pharm Sci. 2019. In press.


  • There are currently no refbacks.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.