title: Thiadiazolodiazepine analogues as a new class of neuromuscular blocking agents: Synthesis, biological evaluation and molecular modeling study.
abstract: The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which could be reversed by the anticholinesterase - Physostigmine. Compounds GS-53 (30) and AAH1 (33) induced dose-dependent neuromuscular blockade with onset time of 3 and 10 min, ED500.15 and 0.36 mmol/kg i.p., respectively, in rats. Compound 30 proved to be as twice as potent as 33 with rapid onset and shorter duration (P < 0.05). Docking profile of 30 and 33 closely resembles HIE-124 (3), in α7β2 nAChR receptor. Molecular modeling analysis indicated that hydrogen bonding to Thr120 and Thr124 beside hydrophobic interactions play effective role incorporating the active ligands to nAChR. The obtained model could be useful for further development of new skeletal muscle relaxants.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: subbagh@yahoo.com.
authors.forename: Hussein I
authors.initials: HI
authors.lastname: El-Subbagh
authors.affiliation: 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.
authors.forename: Adel S
authors.initials: AS
authors.lastname: El-Azab
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 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.
authors.forename: Alaa A-M
authors.initials: AA
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, P.O.Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Kamal E H
authors.initials: KEH
authors.lastname: El-Taher
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D002645:Chickens; D015195:Drug Design; D008297:Male; D062105:Molecular Docking Simulation; D009466:Neuromuscular Blocking Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D009466:Neuromuscular Blocking Agents; D013830:Thiadiazoles; D000110:Acetylcholinesterase
keywords: Molecular modeling study; Neuromuscular blocking agents; Synthesis; Thiadiazolodiazepine analogues