Synthesis, biological evaluation and molecular modeling study of thiadiazolo[3,2-a][1,3]diazepine analogues of HIE-124 as a new class of short acting hypnotics

Hussein I El-Subbagh; Ghada S Hassan; Kamal E H El-Taher; Shahenda M El-Messery; Adel S Al-Azab; Alaa A-M Abdelaziz; Mohamed M Hefnawy

doi:10.1016/j.ejmech.2016.08.038

Synthesis, biological evaluation and molecular modeling study of thiadiazolo[3,2-a][1,3]diazepine analogues of HIE-124 as a new class of short acting hypnotics

Eur J Med Chem. 2016 Nov 29:124:237-247. doi: 10.1016/j.ejmech.2016.08.038. Epub 2016 Aug 22.

Authors

Hussein I El-Subbagh¹, Ghada S Hassan², Kamal E H El-Taher³, Shahenda M El-Messery⁴, Adel S Al-Azab⁵, Alaa A-M Abdelaziz⁶, Mohamed M Hefnawy⁷

Affiliations

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, Cairo 12311, Egypt. Electronic address: subbagh@yahoo.com.
² Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
³ Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁴ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁵ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

PMID: 27597405
DOI: 10.1016/j.ejmech.2016.08.038

Abstract

A new series of 6,7-dihydro-[1,3,4]thiadiazolo[3,2-a][1,3]diazepine analogues were synthesized, and biological evaluated. Compound GS-62 (33) exhibited potent in vivo short acting hypnotic activity with onset time, duration of sleep and therapeutic index of 6.4 ± 0.2, 94.8 ± 5.3 min, 6.62, respectively), in comparison to thiopental sodium (6). Compounds 33 did not show any sign of acute tolerance reported with the maintenance dose of 6. Meanwhile 33 potentiated the in vivo hypnotic effect of 6 in an equimolar amounts (0.06 mmol) combination showing an onset and duration of 7.5 ± 1.3, 62.5 ± 5.9 min, respectively. This combination allowed the use of lower doses of both drugs to avoid the undesirable side effects. Docking studies revealed favorable interactions and binding to BDZ binding site of the GABA_A receptor especially with Arg87, Arg149, and Thr151 amino acid residues.

Keywords: Molecular modeling study; Short acting hypnotic agents; Synthesis; Thiadiazolodiazepine analogues.

MeSH terms

Animals
Azepines / chemical synthesis*
Azepines / chemistry
Azepines / pharmacology*
Carboxylic Acids / chemical synthesis*
Carboxylic Acids / chemistry
Carboxylic Acids / pharmacology*
Chemistry Techniques, Synthetic
Hypnotics and Sedatives / chemical synthesis*
Hypnotics and Sedatives / chemistry
Hypnotics and Sedatives / pharmacology*
Male
Mice
Models, Molecular*
Protein Conformation
Receptors, GABA-A / chemistry
Receptors, GABA-A / metabolism
Sleep / drug effects
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

8-oxo-5,6,7,8-tetrahydro-thiazolo(3,2-a)(1,3)diazepin-3-carboxylate
Azepines
Carboxylic Acids
Hypnotics and Sedatives
Receptors, GABA-A
Thiazoles