Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists

Zarghi, Afshin; Faizi, Mehrdad; Shafaghi, Bijan; Ahadian, Avideh; Khojastehpoor, Hamid R.; Zanganeh, Vahideh; Tabatabai, Sayyed Abbas; Shafiee, Abbas

doi:10.1016/j.bmcl.2005.04.018

Cited by 56 publications

(24 citation statements)

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“…These results are in good agreement with the classical SAR data of BZDs 22) and our previous studies on 1,3,4-oxadiazoles. [13][14][15] In the series of 2-alkylthio oxadiazoles, compounds 5a and 5b possessing a small alkylthio group at C-2 of 1,3,4-oxadiazole ring had moderate anticonvulsant activity in both models. Increasing the size of alkyl group (5c-f) significantly decreases the anticonvulsant activity in both PTZ and MES models.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Zarghi

Hajimahdi

Mohebbi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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

Zarghi

Hajimahdi

Mohebbi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Сполуки, що містять 1,3,4-окса-діазольне ядро, мають широкий спектр біологіч-ної активності, включаючи антибактеріальну [3], фунгіцидну [4], протизапальну [5], анестезуючу [6], антивірусну [7], протиракову [8], антигіпер-тензивну [9], протисудомну [10] та гіпоглікеміч-ну активність [11]. У ряду похідних, що містять 1,3,4-оксадіазол, також відомі сполуки з потуж-ним арсеналом селективної біологічної дії.…”

Section: Issn 2308-8303 (Print) Issn 2518-1548 (Online)unclassified

Synthesis of heteryl derivatives of 2,5-disubstituted 1,3,4-okasadiazole

Karpenko

Omelyanchik

2017

J. org. pharm. chem.

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Синтез гетерилопохідних 2,5-дизаміщених 1,3,4-оксадіазолівНа сучасному етапі розвитку органічної хімії відомо багато основних синтетичних підходів до синтезу по-хідних 1,3,4-оксадіазолів з широким спектром біологічної активності. Гетероциклічні системи, що містять 1,3,4-оксадіазольне ядро, мають багату синтетичну історію і характеризуються наявністю широкого набору ме-тодів синтезу. В оглядовій статті вперше систематизовані та узагальнені літературні джерела, які стосуються хімії гетерилопохідних 2,5-дизаміщених 1,3,4-оксадіазолів як важливих синтетичних субстратів та попередників для конструювання біологічно активних речовин. Розглянуті основні підходи до синтезу даного ряду сполук, які полягають у внутрішньомолекулярній дегідратації 1,2-діацилгідразинів, взаємодії гідразидів гетерилкарбонових кислот з карбонілдихлоридом, ортоетерами, карбону (IV) сульфідом та формуванням оксадіазольного ядра на базі функціональних ацилтіосемікарбазидів та гідразонів. Вагомі акценти зосереджені на реакції циклодегідратації N,N'-діацилгідразидів з використанням дегідратуючих агентів, яка є потужним інструментом конструювання їх синтетично та біологічно привабливих похідних. Детально проаналізовані методи одержання похідних акридону, що містять 1,3,4-оксадіазольний фрагмент, окреслені їх препаративні межі та розкрито біологічний потенціал. Доречно відзначити, що процеси гетерилфункціоналізації є новими в хімії 1,3,4-оксадіазолів і дають змогу отримувати нові біоперспективні гібридні структури. Аналіз даних літератури показує, що похідні 2,5-дизаміще-них 1,3,4-оксадіазолів розглядаються як перспективні речовини з антибактеріальною, фунгіцидною, проти-запальною, гіпоглікемічною, протималярійною активністю. Пошук біологічно активних речовин у даному ряду сполук є доцільним, має практичну і теоретичну значимість.Ключові слова: синтез; 2,5-дизаміщені 1,3,4-оксадіазоли; біологічна активність Y. V. Karpenko, L. O. Omelyanchik Synthesis of heteryl derivatives of 2,5-disubstituted 1,3,4-okasadiazoleAt the present stage of development of organic chemistry there are a lot of basic synthetic approaches to synthesis of 1,3,4-oksadiazole derivatives with a wide spectrum of biological activity. The heterocyclic systems which contain 1,3,4-oksadiazole nucleus have a rich synthetic history and they are characterized by a wide range of methods of synthesis. In the review for the first time have been systematized and summarized literature sources for the chemistry of heteryl derivatives of 2,5-disubstituted 1,3,4-oxadiazole as important synthetic substrates and precursors for the design of biologically active substances. There have been considered the main approaches to synthesis of this series of compounds, which consist in the intramolecular dehydration of 1,2-diacylhydrazine, in the interaction of hydrazides of heterylcarbonic acids with carbonyl dichloride, orthoethers, carbon (IV) sulfide and in the formation of an oxadiazole nucleus based on functional acylthiosemicarbazide and hydrazone. A significant emphasis is concentrated on the cyclodeh...

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“…Oxadiazole is considered to be derived from furan by replacement of two methane (-CH=) group by two pyridine type nitrogen (-N=). There are four possible isomers of oxadiazole (1,2,3,4) depending on the position of nitrogen atom in the ring and are numbered as shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

“…convulsion tests showed that the introduction of an amino group in position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at para position of benzylthio moiety had the best anticonvulsant activity [2] (Figure 2). …”

Section: Anticonvulsant Activitymentioning

confidence: 99%

Latest Update on Pharmacological Activities of 1,3,4-Oxadiazole Derivatives

Kumar¹,

Kumar²

2016

J Cell Sci Ther

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Heterocyclic compounds have been an interesting area for the study of synthesis and biological activity of novel oxadiazole derivatives for a long time. Heterocyclic compounds possess diverse biological properties that have led to intense study and research of these compounds. One of these compounds 1,3,4-Oxadiazole is a versatile heterocyclic nucleus is a novel molecule which attract the medicinal chemist to search a new therapeutic molecule. 1,3,4-oxadizole exhibited a wide range of biological activities which includes antimicrobial activity, anti-tubercular, anticonvulsant, antidiabetic, anti-allergic, enzyme inhibitors, anti-HIV activity, antipyretic activity, Immunosuppressive activity, Spasmolytic Activity, antioxidant activity, Anti-Alzheimer's activity cardiovascular acivity, anti-inflammatory, anti-tumor activity, insecticidal activity, CGRP receptor antagonists, anti-anthelmintic activities. Results of various derivatives of different oxadiazole and their substitutions with diverse biological activities are reviewed in present article.

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Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists

Cited by 56 publications

References 12 publications

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

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

Synthesis of heteryl derivatives of 2,5-disubstituted 1,3,4-okasadiazole

Latest Update on Pharmacological Activities of 1,3,4-Oxadiazole Derivatives

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