Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Synthesis, Molecular Docking, and Antiepileptic Activity of New N-Phthaloylglycine Derivatives Publisher



Khademi M1 ; Moradkhani F2 ; Hosseini FS2 ; Asadi M2 ; Amanlou A3 ; Khorasani R4 ; Morgani AB5 ; Amanlou M2, 3
Authors
Show Affiliations
Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran
  2. 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of the Iranian Chemical Society Published:2022


Abstract

Thalidomide (α-N-phthalimido-glutarimide), the withdrawn sedative compound, has recently been reemerged as a potent agent against epilepsy. In this study, five l-amino acid derivatives of N-phthaloylglycine were synthesized and were tested on pentylenetetrazole (PTZ) induced seizure mice model. N-phthaloylglycine was prepared by reaction of phthalic anhydride and glycine in the presence of triethylamine in toluene under reflux. Arginine, glutamine, leucine, phenylalanine, and tryptophan methyl ester were prepared and coupled with N-phthaloylglycine using coupling agents (EDC and HOBt). The final compounds were characterized by spectroscopic methods (1H NMR, 13 CNMR, IR, and MS). A docking study using AutoDock 4.2 was performed to predict the possible interactions of synthesized compounds on the GABAA receptor. All compounds were characterized, docked into the binding pocket of the GABAA receptor, and tested on pentylenetetrazole-induced seizures in mice. As expected, in silico studies demonstrated that all compounds interact efficiently with the GABAA receptor. All synthesized compounds showed satisfactory results leading to increased latency time to the first symptom of a seizure. The phenylalanine methyl ester derivative of N-phthaloylglycine (6d) had antiepileptic effects even more potent than thalidomide. Increasing lipophilicity and facilitating compounds delivery through l-amino acid carriers to the brain appear to be responsible for the remarkable activity of these compounds. Both in silico and in vivo results suggest that the l-amino acid derivatives of N-phthaloylglycine act as a novel compound against chemically induced seizures through interaction with the binding pocket of the GABAA receptor. © 2021, Iranian Chemical Society.