Thiadiazolodiazepine analogues as a new class of neuromuscular blocking agents: Synthesis, biological evaluation and molecular modeling study

The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2a][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, ED50 0.15 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 alpha 7 beta 2 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. (C) 2016 Elsevier Masson SAS. All rights reserved.