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New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor

Medicinal Chemistry Research volume 25, pages 1538–1550 (2016)Cite this article

Abstract

A new method for the synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (alprazolam) and 7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (diazepam) from 2-amino-5-chloro benzophenone was described under mild conditions. Most of the synthetic steps were carried out under solvent-free conditions, and the products were obtained in high yield and purity. The products were characterized by comparison of physical properties with authentic samples and also by IR, 1H NMR and 13C NMR. Three-dimensional (3D) model of GABAA was constructed using X-ray crystal structure of homopentameric caenorhabditis elegans glutamate-gated chloride channel (GluCl) (3RHW) at 3.3 Å as the template based on sequence comparison and homology modeling method. The homology modeling and MD simulation studies predicted the 3D structure of receptor in a water environment. The resulted conformation of the receptor was used for docking of the alprazolam and diazepam. Docking studies indicated many important interactions of the drugs with the receptor. Furthermore, the complex of GABA with drugs was used in MD simulation to realize the conformation changes of the complex.

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Acknowledgments

We appreciate financial support of Shahreza Branch, Islamic Azad University (IAUSH) Research Council.

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Authors and Affiliations

  1. Department of Chemistry, Shahreza Branch, Islamic Azad University, Shahreza, Isfahan, 86145-311, Iran

    Ahmad R. Massah, Hamid Ardeshiri Lordejani & Nahad Asakere

  2. Razi Chemistry Research Center, Islamic Azad University, Shahreza Branch, Shahreza, Isfahan, 86145-311, Iran

    Ahmad R. Massah

  3. Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran

    Sajjad Gharaghani

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  1. Ahmad R. Massah
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Correspondence to Ahmad R. Massah.

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Massah, A.R., Gharaghani, S., Lordejani, H.A. et al. New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor. Med Chem Res 25, 1538–1550 (2016). https://doi.org/10.1007/s00044-016-1585-z

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Keywords

  • Alprazolam
  • Diazepam
  • GABA
  • Homology modeling
  • Molecular docking
  • Molecular dynamics simulation