Synthesis of 5-(2-,3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity

New S-alkylated 5-(2-,3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiols (5a-c, 6a-c) and 5-(2-,3- and 4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols (7a-c, 8a-c, 9a-c) were synthesized by the alkylation of 3-(2-,3- and 4-methoxyphenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones (3a-c) or 3-(2-,3- and 4-methoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones (4a-c) with 1-iodobutane or 1-(1,3-benzodioxol-5-yl)-2-bromo-1-ethanone, 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone and 2-bromo-1-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-ethanone. Compounds 3a-c and 4a-c were synthesized by the acylation of thiosemicarbazide or 4-phenyl-3-thiosemicarbazide with 2-, 3- and 4-methoxybenzoyl chlorides and further cyclization of the obtained acylderivatives 1a-c and 2a-c. The synthesized compounds 4a-c, 5a, 6a-c, 7a-c, 8a-c, 9b,c exhibit anti-inflammatory activity.     

The in vivo metabolism of 5-(4-nitrophenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione in rats

It is known that substituted 1,2,4-triazole-3-thione derivatives have several biological activities, such as antimicrobial, diuretic and antidepressant activities. In our previous studies, the antifungal activity of 5-(4-aminophenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione was found to be active against Candida tropicalis K1022. The aim of this study was to investigate the in vivo metabolic pathway of 5-(4-nitrophenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione which was selected as a model compound for this study. The substrate and its potential metabolites, i.e. the acetylation and nitro reductive products, were synthesized and then separated using HPLC on a reverse phase system. In the in vivo metabolism study, a 4 mg dose was administered i.p. to male Wistar rats. Blood samples were collected at 0, 2, 4, 8, 12, 24 and 56 hours after administration and were passed through a Sep-Pak cartridge. The acetylated metabolite [5-(4-acetylaminophenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione ], the amine metabolite [5-(4-aminophenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione] and an unknown metabolite were detected.     

The in vivo metabolism of 5-(4-nitrophenyl)-4-(2-phenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione in rats.

The purpose of this study was to investigate the in vivo metabolism of 5-(4-nitrophenyl)-4-(2-phenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione. First its potential metabolites were synthesized and then the structures of the original compound were elucidated by UV, 1H-NMR and elemantary analysis. 40 mg dose was given intraperitoneally to rats. Blood samples were collected at 0, 0.5, 1, 2, 4, 6, 12, 24, 48 and 72 hours after administration of substrate and blood was centrifuged to obtain plasma. The plasma were passed through a Sep-Pak C18 cartridge. The samples were separated using HPLC on a reverse phase system. This study revealed reduction, N-acetylation and N-dealkylation as pathway of 5-(4-nitrophenyl)-4-(2-phenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione metabolism.     

Synthesis of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives of potential anti-inflammatory activity

A series of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives 4-10 were synthesized by rearrangement of 4-(3-pyridyl)-hydrazono-2-phenyl-2-oxazolin-5-one 3 in the presence of different nucleophiles to afford derivatives 4, 7, and 8, while hydroxamic acid derivative 6 was prepared from reaction of methyl ester 4 with hydroxylamine hydrochloride. Semicarbazide 9 and thiosemicarbazide 10, derivatives of the 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid, were synthesized via hydrazide 8 with potassium cyanate and appropriate isothiocyanate, respectively. The structures of the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR, and mass spectra. The results of the anti-inflammatory activity of the synthesized derivatives showed that most of the tested compounds 4-10 showed significant inhibition against carrageenan-induced rat paw edema in albino rats. Derivatives 4 and 8 showed promising results and were found to be equipotent or more potent than Indomethacin and Celecoxib as reference drugs at two dose levels, 5 and 10 mg/kg, and they have no ulcerogenic activity.     

Synthesis of some novel azo derivatives of 3,5-dimethyl-1-(2-hydroxyethyl)pyrazole as potent analgesic agents

A series of 1-(2-hydroxyethyl)-3,5-dimethylpyrazolylazo derivatives, incorporating thiosemicarbazide 2a-c, 1,3,4-thiadiazole 3a-c, and 1,2,4-triazole-3-thione 4a-c were synthesized. The structure of these novel synthesized compounds 2a-c, 3a-c, and 4a-c was confirmed by spectral analysis. All these compounds were screened for their analgesic activity. Hot-plate and tail-immersion tests were used for the determination of the analgesic activity. Morphine, an analgesic through both spinal and supraspinal pathways, was used as a standard test drug. All compounds were administered at a dose of 100 mg/kg i.p. Among the compounds, 2-(butylamino)-5-[((1-(2-hydroxyethyl)-3,5-dimethylpyrazole-4-yl)azo)phenyl]-1,3,4-thiadiazole 3a and 4-[((1-(2-hydroxyethyl)-3,5-dimethylpyrazole-4-yl)azo)phenyl]-4-(2-phenethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 4c showed analgesic effects in both tests. Especially 4c exerted strong analgesia starting at 30 min after injection.     

5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮的合成

丙酰肼与三光气缩合环化得到5-乙基-1,3,4-噁二唑-2(3H)-酮,继与2-苯氧乙胺反应后在碱性条件下环合得到抗抑郁药奈法唑酮中间体5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮,总收率66.3%.     

Synthesis,characterization, and screening for analgesic and anti-inflammatory activities of new 1,3,4-oxadiazole derivatives linked to quinazolin-4-one ring

In the present study, several new 1,3,4-oxadiazole derivatives linked with quinazolin-4-one moiety were synthesized by following steps. 2-methyl -4H-3, 1-benzoxazin-4-one, and 2-phenyl -4H-3, 1-benzoxazin-4-one were synthesized in the first and second step by stirring anthranilic acid in pyridine with benzoyl chloride and with an acetic anhydride for 30?min at room temperature. On treatment with semicarbazide with the above synthesized intermediates, that is, 2-methyl-4H-3,1-benzoxazin-4-one, and 2-phenyl-4H-3,1-benzoxazin-4-one in the third step afforded 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide. These were introduced in cyclization reaction with different aromatic acids, aromatic aldehydes, and carbon disulfide in the next step, producing the corresponding 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-phenyl-quinazolin-4(3H)-one derivatives, 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-quinazolin-4(3H)-one derivatives, 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one derivatives and 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-methylquinazolin-4(3H)-one derivatives. Purity of these synthesized derivatives was confirmed by thin layer chromatography, melting point. Structure of the derivatives was set up by determining infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All the synthesized derivatives were evaluated for their analgesic and anti-inflammatory activities in mice and rats. In animal studies, the derivatives 3-[4-acetyl-5-(2-hydroxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one shown more potent analgesic activity and the derivatives 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-methylquinazolin-4(3H)-one shown more potent anti-inflammatory activity as compared to other derivatives. The results of current study indicate that cyclization of carbohydrazide group of intermediate 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide with different aromatic acids, aromatic aldehydes, and carbon disulfide produces novel quinazolin-4-one linked oxadiazole derivatives with potent analgesic and anti-inflammatory activities.     

Synthesis and tuberculostatic activity of some (4-phenylpiperazin-1-ylmethyl)-1,3,4-oxadiazole and (4-phenylpiperazin-1-ylmethyl)-1,2,4-triazole derivatives

The phenylpiperazineacetic hydrazide cyclization product. 5-(4-phenylpiperazin-1-ylmethyl)-1,3,4-oxadiazole-2-thiol (1) upon alkylation gave the S-methyl derivative (2). next it was tranmsformed into 1-phenyl-4-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-ylmethyl)-piperazine (3). Upon the reaction of I with 1.2-dibromoethane. the derivative (4) containing two joint 1,3,4-oxadiazole systems was obtained. The reactions of compound 1 with chloroacetonitrile and chloroacetic acid gave the corresponding nitrile and carboxylic acid (5, 6) as well. The 4-amino-1,2,4-triazole-3-thiol derivative (7) was obtained in the reaction of compound I with hydrazine hydrate. The phenylpiperazinacetic acid hydrazide was transformed into 1,3,4-oxadiazol-2-ylamine (8), and this, subsequently, into the 2-ethoxy-1,2,4-triazole derivative (9). The compounds obtained were tested in vitro for their tuberculostatic activity. The minimum inhibiting concentrations (MIC) were within 25 - 100 mg/ml.     

Synthesis of some thiazole-, 1,3,4-thiadiazole-, and 4H-1,2,4-triazole derivatives of pyrazolo[3,4-b]quinoline

Three novel series of pyrazolo[3,4-b]quinolines were prepared, namely: 1-(3-substituted-4-phenylthiazolin-2-ylidene)hydrazinocarbonylm ethyl-1H-pyrazolo[3,4-b]quinolines 3a-d; 1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methyl-1H-pyrazolo[3,4-b]quinolines 4b-d, and 1-(4-substituted-4H-5- thioxo-1,2,4-triazole-3-yl)methyl-1H-pyrazolo[3,4-b]quinolines 5a-d. These compounds were prepared by cyclization of the new key intermediates 1-(substituted thiocarbamoylhydrazinocarbonyl)methyl-1H- pyrazolo[3,4-b]quinolines 2a-d. The alkylthio, aralkylthio 6a-f as well as the Mannich bases 8a-f derived from compounds 5a-d were also prepared. The structures of the new compounds were elucidated by elemental analyses, IR, 1H-NMR-, and mass spectra. The antimicrobial as well as inotropic and chronotropic activities were studied.     

Synthesis and monoamine oxidase inhibitory activities of 1-thiocarbamoyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole derivatives

Ten new 1-thiocarbamoyl-3-(phenyl and/or 4-substituted phenyl)-5-(3,4-dimethoxyphenyl and/or 2-chloro-3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole derivatives were synthesized by reacting 1,3-diphenylpropen-1-ones and thiosemicarbazide. The chemical structures of the compounds were verified by means of their IR, 1H-NMR, ESI-MS spectroscopic data and elementary analyses. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in-vitro tests. Monoamine oxidase was isolated and purified from the mitochondrial extracts of rat-liver homogenates and human platelets. Monoamine oxidase inhibitory activities of the compounds were compared with pargyline and clorgyline. Most of the compounds inhibited the total activity of rat liver homogenates. The monoamine oxidase-A inhibitory effects of 1-thiocarbamoyl-3-(4-methoxyphenyl)-5-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole and 1-thiocarbamoyl-3-(4-methoxyphenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole were detected as potent as clorgyline. Selective and irreversible inhibition of rat liver monoamine oxidase-A by synthesized compounds have promising features for designing the new selective monoamine oxidase A inhibitors as potent and reliable anti-depressants in the future.     

Synthese und Eigenschaften von 4-Alkyl-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-5-onen

Synthesis and Reactions of 4-Alkyl-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepine-5-ones The synthesis of the 4-alkyl-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepine-5-ones (1a) by reductive cyclisation of the corresponding 2-nitro-N-alkyl-N-phenacylbenzamides (5) is reported. The different reactions of the new 4-alkyl-derivatives and the known 4-unsubstituted compounds of this ring system are described.     

Synthesis and calcium antagonistic activities of fecal metabolites of a new calcium antagonist (+)-(R)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N- [2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4- methyl-3-oxo-2H-1,4-benzothiazine (SD-3211) in rats

In order to confirm the structure of three fecal metabolites, M-I, M-II and M-III, of a new calcium antagonist, (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4- benzothiazine (SD-3211), in rats, (+)-3,4-dihydro-2-[5-hydroxy-2-[3-[N-methyl-N-[2- [(3,4-methylenedioxy)-phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl- 3-oxo-2H-1,4-benzothiazine((+)-I), (+)-3,4-dihydro-2-[5-hydroxy-2-[3-[N- [2-[(3,4-methylenedioxy) phenoxy]ethyl]amino] propoxy]-phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine((+)-II) and (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4- benzothiazine((+)-III) were synthesized. Compounds (+)-I, (+)-II and (+)-III were identified with the fecal metabolites M-I, M-II and M-III, respectively. The calcium antagonistic activities of (+)-I, (+)-II and (+)-III were examined.     

2-(3,4-二甲氧基苯基)-3-甲基丁腈合成工艺的改进

目的合成2-(3,4-二甲氧基苯基)-3-甲基丁腈并进行工艺改进。方法以3,4-二甲氧基乙腈和2-溴丙烷为原料,筛选相转移催化剂,进行烃化反应得到目标物。结果以四丁基溴化铵为催化剂,收率为82%,产物结构经熔点和核磁共振氢谱确认。结论所改进的合成路线操作简单,适合工业化生产。     

Synthesis and antimicrobial activity of 3-(4'-hydroxy-3'-methylphenyl)-5-[(substuted) phenyl]-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone derivatives

A series of 3-(4'-hydroxy-3'-methylphenyl)-5-[(substituted) phenyl]-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone derivatives were synthesized by the reaction between isoniazid (INH) and various chalcones and were tested for their antimicrobial activity in vitro against Staphylococcus aureus 209p, Escherichia coli ESS 2231, Aspergillus fumigatus, Candida albicans, Candida albicans ATCC 10231, Candida krusei GO3 and Candida glabrata HO5. Among the synthesized compounds, all the compounds possess the significant antibacterial activity. Compounds I(III) and I(x), i.e. 3-(4'-hydroxy-3'-methylphenyl)-5-(4"-dimethylaminophenyl)-4,5-dihydro-1H-1-pyrazolyl-4-pyridyl methanone and 3-(4'-hydroxy-3'-methylphenyl)-5-(2",6"-dichlorophenyl)-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone were found to be the most active agents against used bacterial and fungal strains with minimum inhibitory concentration of less than 0.5 microg/mL and were equally active as standard drugs Ofloxacin and Fluconazole.     

Synthesis of 1-(3-amino-2-hydroksypropyl)-4-phenyl-1,2,4-triazolin-5-one and 1-(3-amino-2-hydroksypropyl)-3,4-diphenyl-1,2,4-triazolin-5-one derivatives

In the reaction of 4-phenyl-1,2,4-triazolin-5-one [Ia] and 3,4-diphenyl-1,2,4-triazolin-5-one [Ib] with 1-chloro-2,3-epoksypropane, the respective derivatives of 1-(2,3-epoksypropane)-4-phenyl-1,2,4-triazolin-5-one [IIa] and 1-(2,3-epoksypropane)-3,4-diphenyl-1,2,4-triazolin-5-one [IIb] were obtained. Then these compounds were converted into the corresponding aminoalkanol derivatives of 1,2,4-triazolin-5-one [IIIa, b-VIIIa, b] in reaction with secondary amines. The new compounds affected significantly the central nervous system of mice.     

Synthesis of 1-(3-aminopropyl)-4-phenyl-1,2,4-triazolin-5-one and 1-(3-aminopropyl)-3,4-diphenyl-1,2,4-triazolin-5-one

The reaction of 4-phenyl-1,2,4-triazolin-5-one [Ia] and 3,4-diphenyl-1,2,4-triazolin-5-one [Ib] with 1-bromo-3-chloropropane was carried out. The obtained compounds [IIa, b] were subjected to the reaction with secondary amines and ethylenediamine with resulted in 1-(3-aminopropyl)-1,2,4-triazolin-5-one derivatives.     

Synthesis of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semi-carbazides and their transformation into 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides as potential anticancer and anti-HIV agents

Synthesis of a series of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semicarbazides (6-16) and 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides (17-22) were reported. Compounds 7-9, 17, 19-22 were tested at the US National Cancer Institute for their in vitro anticancer and anti-HIV activities. Results of anticancer screening showed moderate activity of 21 and 22, while 19 was found to have encouraging anti-HIV activity at EC(50) = 28.8 microM.     

Synthesis of benzimidazole derivatives as potential antimicrobial agents

Three novel series of benzimidazol derivatives were prepared. Namely; 2-alkyl-1-(4-substituted-4H-1,2,4-triazole-5-thion-3-yl)methylb enzimidazoles; 2-alkyl-1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methylbenzimidazoles; and 2-alkyl-1-[(3,4-disubstituted thiazolin-2-ylidene)hydrazinocarbonyl] methylbenzimidazoles. The antimicrobial testing of the prepared compounds as well as of the key intermediate thiosemicarbazides was performed.     

Synthesis and biological studies of triazolo-/thiadiazolo-benzoxazines

Diethyl bromomalonate (2) with an equimolar amount of 2-aminophenol (1) in the presence of sodium fluoride undergoes a cyclization reaction to form 2H,4H-2-ethoxycarbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (3). Furthermore, compound 3 undergoes a condensation reaction with hydrazine hydrate in the presence of methanol to yield 2H,4H-2-hydrazinocarbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (4), which on further reaction with aryl isothiocyanates gave 2H,4H-2-[ (4'-substituted)-phenylthiosemicarbazino]-carbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (5). Compound 5 on treatment with NaOH, cone. H2SO4 and diethylmalonate (6). afforded 2H,4H-2-[2'H-3'-thioxo-4'-substituted phenyl-1',2',4'-triazole-5-yl]- 3,4-dihydro-3-oxo-1,4benzoxazine (7). 2H,4H-2-[2'-amino-(substituted)-phenyl-1,3',4'-thiadiazol-5-yl]-3,4-dihydro-3-oxo-1,4-benzoxazine (8) and 2H,4H-2-[5'H-5'-dihydro-2'-thioxo-3'-phenyl-4',6'-dioxo-1,3-diazine]-aminocarbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (9), respectively. The synthesized compounds were investigated for their antibacterial activities against Gram positive as well as Gram negative bacteria with ampicillin trihydrate as standard drug. Structures have been elucidated on the basis of spectral and chemical analyses.     

Synthesis and anti-inflammatory activity of 1-acylaminoalkyl-3,4-dialkoxybenzene derivatives

New 1-acylaminoalkyl-3,4-dialkoxybenzene derivatives 17-31 were synthesized by the acylation of amines 9-16 with acyl chlorides. Amines 9-16 were obtained from aryl ketones 1-8. Aryl ketones 1-8 were synthesized by the acylation of corresponding aromatic compounds. As it was preliminary predicted by PASS (Prediction of Activity Spectra for Substance) program, all 1-acylaminoalkyl-3,4-dimethoxy- and 3,4-diethoxybenzene derivatives possess anti-inflammatory activity. Activity of compounds 18, 19, 21, 24, 26, 27, 28, 29 was similar to that of acetylsalicylic acid or ibuprofen however their acute toxicity was less than that of mentioned anti-inflammatory drugs. A series of 1-acylaminoalkyl-3,4-dimethoxybenzene, 1-acylaminoalkyl-3,4-diethoxybenzene and 6-acylaminoalkyl-2,3-dihydro-1,4-benzodioxine derivatives have been synthesized. These compounds possess moderate or strong anti-inflammatory activity and low toxicity.