Synthesis, biological evaluation and molecular modeling study of some new thiazolodiazepine analogs as CNS active agents

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• 作者：Sarah T.A. Al-Rashood^a ; Ghada S. Hassan^b ; Shahenda M. El-Messery^c ; Kamal E.H. El-Taher^d ; Mohamed M. Hefnawy^a ; Mahmmed A. Al-Omar^a ; Hussein I. El-Subbagh^b ; ^e ; ^{subbagh@yahoo.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Synthesis ; Thiazolodiazepine analogs ; CNS activity ; Molecular modeling study
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：26
• 期：2
• 页码：445-453
• 全文大小：1728 K

文摘

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 (0.78 mmol/kg) and 20 (0.39 mmol/kg) showed remarkable 100% protection against PTZ induced convulsions with two and four fold increase in activity than sodium valproate (1.38 mmol/kg), respectively. Molecular modeling studies showed hydrogen bonding interaction between 15 and Thr56 residues at the binding site of GABA_A. 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.