Design and Synthesis of New 2-Substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as Anticonvulsant Agents

Abstract

The benzodiazepines (BZDs) are widely used in the treatment of central nervous system (CNS) disorders such as anxiety, insomnia and epilepsy.1) The pharmacological effects of the BZDs result from their affinity for a specific binding domain on the gamma amino butyric acid (GABA A ) receptors, known as the BZD receptor. The interaction of BZD agonists with GABA A receptor complex increases the GABA-induced chloride channel opening frequency, which results in membrane hyperpolarization, thus reducing neuronal excitability.2,3) The BZD binding sites in the brain were identified and described by radioligand receptor binding assays and originally it was found that only 1,4-BZD derivatives bind to these receptors. It has since been shown that many groups of compounds bind to the BZD receptor with high affinity, e.g., triazolopyridazines, cyclopyrrolones, quinolines and b-carbolines.4-7) Several pharmacophore models have been proposed for BZDs, and amongst all models suggested for binding to the BZD receptor at least two features are common: an aromatic ring and a coplanar proton accepting group in suitable distance (5 Å). Also, the presence of a second out-ofplane, aromatic ring could potentiate binding to the receptor. [8][9][10][11][12] On this basis, a wide variety of compounds with a chemical structure different from that of BZDs have been synthesized and tested. We recently started a wide research program aimed to design new BZD receptor ligands characterized by a higher degree of flexibility compared with classic BZD ligands. Accordingly, we reported several 1,3,4-oxadiazole derivatives which showed considerable anticonvulsant activity. [13][14][15] As part of our ongoing research program to design new anticonvulsant agents, we describe herein the synthesis and biological evaluation of a novel group of 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles ( Fig. 1) with a flexible second out-of-plane aromatic ring, benzyloxy group which has all the suggested requirements for binding to the BZD receptors. Results and DiscussionChemistry The target 1,3,4-oxadiazole derivatives were synthesized according to Chart 1. Accordingly, reaction of 2-halo-2-benzyloxy benzoic acid methyl ester 1 with hydrazine hydrate in N,NЈ-dimethyleformamide (DMF) at room temperature afforded corresponding 2-halo-2-benzyloxy benzoic acid hydrazide 2 high yields (87-90%).16) The hydrazide were converted to 2-amino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazoles 3 using cyanogen bromide in methanol (71-90%).17) 5-(2-Halo-2-benzyloxyphenyl)-2-mercapto-1,3,4-oxadiazole 4 was prepared by the reaction of hydrazide 2 with carbon disulfide under basic condition (60-70%). 18)Sonication of compound 5 in the presence of suitable alkyl halide in alkaline media afforded 2-alkylthio-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 5a-f (58-90%). 19)Treatment of hydrazide 2 with phenylisothiocyanate followed by reaction with KI/I 2 in alkaline hydro-ethanol gave 2-anilino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 7 (57-80%).20) The compounds we...

Novel agonists of benzodiazepine receptors: Design, synthesis, binding assay and pharmacological evaluation of 1,2,4-triazolo[1,5-a]pyrimidinone and 3-amino-1,2,4-triazole derivatives

“…In addition, binding to the receptor could be potentiated by second out-of-plane aromatic ring. 6,7 According to this structure-activity relationship (SAR) and in continuance of our previous studies on some simple non-rigid derivatives with five member heterocycle rings such as triazoles, oxadiazoles, and thiadiazoles, 6,[8][9][10][11][12][13][14][15][16] We designed some structures with all suggested requirements ( Fig. 1) and performed conformational analysis followed by superimposition of energy minima conformers of the designed compounds on estazolam, a known BZD agonist to confirm whether they could mimic the structure of a BZD agonist.…”

Novel 4-thiazolidinone derivatives as agonists of benzodiazepine receptors: design, synthesis and pharmacological evaluation

“…Furthermore, the previously reported article revealed that thiazolidinone derivatives exhibit anticonvulsant activity (Tripathi et al, 2014[21]). Based on these evidences and our earlier published papers on flexible novel heterocyclic compounds (Akbarzadeh et al, 2003[1]; Almasirad et al, 2004[4]; Zarghi et al, 2005[24]; Almasirad et al, 2007[5]; Zarghi et al, 2008[22]; Mahdavi et al, 2010[13]; Faizi et al, 2012[7]; Tabatabai et al, 2013[20]; Zarghi et al, 2008[22][23]; Faizi, et al, 2015[6]) , some new thiazolidinone derivatives that have the essential pharmacophore groups for binding to the BZD's receptors were developed (Figure 1(Fig. 1)).…”

“…In MES model, different doses of the novel compounds or diazepam were injected and after 30 minutes, MES were applied (60 Hz, 37.2 mA and 0.25 s) using ear electrodes. We recorded the number of mice protected from hind limb tonic extension (HLTE) induced by MES for data analysis (Zarghi et al, 2005[24], 2008[22]).…”

Improved Protocol Toward 1,3,4-Oxadiazole-2(3H)-thiones and Scale-up Synthesis in the Presence of SDS as a Micelle Promoted Catalyst

“…However, this classical method of preparation generally requires a long period of time (9-36 h). [6][7][8][9][10][11] Long chain aliphatic hydrazinecarbodithioate intermediates have to be heated under reflux for a long time. To the best of my knowledge, however, few studies have reported alternative synthesis methods for the preparation of 1,3,4-oxadiazole derivatives.…”