title: Synthesis, biological evaluation and molecular modeling study of some new thiazolodiazepine analogs as CNS active agents.
abstract: New derivatives of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 3), were synthesized as continuation to our previous patented efforts. Compounds 15 and 20 showed marginal hypnotic potency compared to 3. Compounds 15 (0.78mmol/kg) and 20 (0.39mmol/kg) showed remarkable 100% protection against PTZ induced convulsions with two and four fold increase in activity than sodium valproate (1.38mmol/kg), respectively. Molecular modeling studies showed hydrogen bonding interaction between 15 and Thr56 residues at the binding site of GABAA. Superposition, flexible alignment and surface mapping of 15, 20 and diazepam supports their biological resemblance where ADMET study suggested that those compounds could be used as oral anticonvulsants.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Sarah T A
authors.initials: STA
authors.lastname: Al-Rashood
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.affiliation: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Shahenda M
authors.initials: SM
authors.lastname: El-Messery
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Kamal E H
authors.initials: KEH
authors.lastname: El-Taher
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Hefnawy
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Mahmmed A
authors.initials: MA
authors.lastname: Al-Omar
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311 Cairo, Egypt. Electronic address: subbagh@yahoo.com.
authors.forename: Hussein I
authors.initials: HI
authors.lastname: El-Subbagh
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001381:Azepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002264:Carboxylic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D058785:GABA-A Receptor Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006993:Hypnotics and Sedatives / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008958:Models, Molecular; D010433:Pentylenetetrazole; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C526399:8-oxo-5,6,7,8-tetrahydro-thiazolo(3,2-a)(1,3)diazepin-3-carboxylate; D000927:Anticonvulsants; D001381:Azepines; D002264:Carboxylic Acids; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D013844:Thiazoles; D010433:Pentylenetetrazole
keywords: CNS activity; Molecular modeling study; Synthesis; Thiazolodiazepine analogs