Synthesis and docking study on thiadiazolo[3,2-a][1,3]diazepin-8(5H)-one derivatives as selective GABA(A) agonists

HIE-124 is a new member of ultra-short acting hypnotics’ drug family. In this research, the synthesis of analogues of HIE-124 drug in the heterocyclic thiazole ring replaced to thiadiazole, will be presented. Thiadiazolodiazepines during a two-step reaction starting from the amino thiadiazole resulted from-various derivatives of benzoic acid and thiosemicarbazide were synthesized. In the first step, the reaction of synthetic raw material 2-amino thiadiazole and 4-chlorobutyrilchloride in toluene solvent give the 4-chloro-N-(5-(methyl/aryl)-1,3,4-thiadiazol-2-yl) butanamide intermediate. In the next step, from the cyclization reaction of this intermediate ring in the presence of base under reflux, the target products are synthesized. Structure of products was identified based on IR, HNMR and CNMR spectroscopy analysis. Then, the procedure of docking of ligands were performed on the active site of GABAA that the common residues involved in allosteric modulators such as benzodiazepines and HIE-124 include ASN82, ASN81, PHE79, MET1, TYR106, ALA38 and AlA168. Consequently, These Docking calculations suggest that these new compounds might be having better interaction results between receptor (GABAA) than HIE-124.