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. 2016 Jan 15;26(2):445-453.
doi: 10.1016/j.bmcl.2015.11.097. Epub 2015 Dec 7.

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

Sarah T A Al-Rashood  1 , Ghada S Hassan  2 , Shahenda M El-Messery  3 , Kamal E H El-Taher  4 , Mohamed M Hefnawy  1 , Mahmmed A Al-Omar  1 , Hussein I El-Subbagh  5
Affiliations

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

Sarah T A Al-Rashood et al. Bioorg Med Chem Lett. .

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.

Keywords: CNS activity; Molecular modeling study; Synthesis; Thiazolodiazepine analogs.

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