Synthesis, antiviral, antituberculostic, and antibacterial activities of some novel, 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-(substituted imino)pyrimidines

A variety of novel 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-substituted imino) pyrimidines were synthesized by reacting 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-amino pyrimidines with different substituted aromatic aldehydes, coumarin chloroisatin. The 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-amino pyrimidines were synthesized by reacting 3-(4'-substituted phenyl)-1-(4-nitrophenyl)-2-propen-1-ones with guanine hydrochloride. 3-(4-Substituted phenyl)-1-(4-nitrophenyl)-2-propen-1-ones were synthesized by reacting 4-nitroacetophenone with different para-substituted aromatic aldehydes. Spectral data (IR, NMR, and mass spectra) confirmed the structures of the synthesized compounds. The synthesized compounds were investigated for their antiviral, antituberculostic, and antibacterial activities. The results of antiviral, antituberculostic, and antibacterial activities indicated that the synthesized compounds exhibited mild to potent activities compared to the respective reference standards.     

5-Substituted pyrimidine acyclic nucleoside analogues 1-cyanomethyl- and 1-(4-cyanobutyl)-5-substituted uracils as candidate antitumor agents

A number of 5-substituted pyrimidine acyclic nucleosides were synthesized and tested for in vitro cytotoxicity against four cell lines (J-82 cell, P-388 cell, FM-3A cell and U-938 cell lines). Synthesis of 1-cyanomethyl-5-substituted pyrimidines (1a-e) and 1-(4-cyanobutyl)-5-substituted pyrimidines (2a-e) was accomplished from the series of alkylation reactions of 5-substituted uracils with the corresponding chloroacetonitrile and 5-chlorovaleronitile in DMSO under 50 degrees C temperature. These 5-substituted pyrimidine acylic nucleosides (1a-e and 2a-e) exhibited moderate to significant activity against four cell lines.     

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 and antimicrobial activity of some 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted piperazin-1-yl)acetamido]-2-(p-substituted phenyl)benzoxazoles

In this study, a series of twelve novel 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted pip-erazine-1-yl)acetamido]-2-(p-substituted phenyl]benzoxazole derivatives have been synthesized and their structures were confirmed by IR, (1)H NMR, and mass spectral data. These compounds were prepared by reacting 5-(2-chloroacetamido)-2-(4-p-substituted-phenyl)benzoxazoles, which were obtained by using 5-amino-2-[p-substituted-phenyl]benzoxazoles with chloroacetyl chloride, in the presence of morpholine or 1-substituted piperazines. All synthesized compounds 3-14 were tested by using the method of twofold serial dilution technique for in vitro activities against certain strains of Gram-positive, Gram-negative bacteria as well as the yeasts Candida albicans, Candida krusei, and Candida glabrata in comparison with standard drugs. Microbiological results showed that the newly synthesized compounds possessed a broad spectrum of activity, showing MIC values of 3.12-50 mug/mL against the Candida species.     

New 3-[4-(3-substituted phenyl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants

In this paper a series of new 3-[4-(3-substituted phenyl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propanol derivatives is presented as a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. The 5-HT1A receptor and 5-HT transporter binding affinities of hydroxylic compounds 4 a-e have been determined. The new compounds present nanomolar affinity for both activities, and 1-(benzo[b]thiophen-3-yl)-3-[4-(3-methoxyphenyl)piperazin-1-yl]propan-1-ol (4d) shows values (nM) of Ki = 86 for 5-HT1A receptors and Ki = 76 for the serotonin transporter, respectively.     

Synthesis and antileukemic activity of novel 2-(4-(2,4-dimethoxybenzoyl)phenoxy)-1-(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)ethanone derivatives

A series of novel 2-(4-(2,4-dimethoxybenzoyl)phenoxy)-1-(4-(3-(piperidin-4-yl)propyl) piperidin-1-yl)ethanone derivatives 9(a-e) and 10(a-g) were synthesized and characterized by (1) H NMR, IR, mass spectral, and elemental analysis. These novel compounds were evaluated for their antileukemic activity against two human leukemic cell lines (K562 and CEM) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. Some of the tested compounds showed good antiproliferative activity with IC(50) values ranging from 1.6 to 8.0 μm. Compound 9c, 9e, and 10f with an electron-withdrawing halogen substituent at the para position on the phenyl ring showed excellent in vitro potency against tested human leukemia cells (K562 and CEM).     

Synthesis of 3-substituted phenacyl-5-[2-phenyl-4H-4-oxo-1-benzopyran-6- yl)methylenyl]-thiazolidine-2,4-diones and evaluation of their antimicrobial activity

Synthesis and physico-chemical properties of two 3-substituted phenacyl-thiazolidine-2,4-diones (2c-d) and four 3-substituted phenacyl-5-[2-phenyl-4H-4-oxo-1-benzopyran-6-yl)methyl-enyl]-thiazolidin e- 2,4-diones (4a-d) are described. These products were synthesized by Knoevenagel reaction from flavone-6-carboxaldehyde (3) and 3-(substituted phenacyl)- thiazolidine-2,4-diones (2a-d). Antibacterial and antifungal activities were investigated for these compounds.     

The antioxidant and membrane-stabilizing properties of 1-(4-substituted phenyl)-2h-(phenyl)-3-aminopropan-1-ol hydrochlorides in vitro

In vitro model systems were used to study the antioxidant and membrane-stabilizing properties of 1-(4-substituted phenyl)-2H-(phenyl)-3-aminopropan-1-ol hydrochlorides. These secondary aminopropanols, whose synthesis is first reported here, were found not to have any significant antioxidant or antiradical activity either in an ascorbate-dependent Fe(II)-stimulated peroxidation system, in a method based on the spectrophotometric monitoring of decreases in the concentration of the stable radical 1,1-diphenyl-2-picrylhydrazyl, or in the photochemiluminescence analysis method. However these compounds had marked antihemolytic effects in an erythrocyte oxidative stress model. It is suggested that the new 1-(4-substituted phenyl)-2H-(phenyl)-3-aminopropan-1-ol hydrochlorides are biologically active compounds with weak antioxidant properties, capable of membrane-stabilizing actions due to interaction with the structural components of cell membranes.     

Synthesis and pharmacological investigation of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new class of H1-antihistamine agents

A series of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones was synthesized by the cyclization of 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one with various one-carbon donors. The starting material, 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one, was synthesized from 4-substituted aniline by a novel innovative route. When tested for in-vivo H1-antihistamine activity on conscious guinea-pigs, all the test compounds significantly protected the animals against histamine-induced bronchospasm. The compound 1-methyl-4-(4-chloro phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (VII) was more potent (72.71% protection), and 1-methyl-4-(4-methoxy phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) was equipotent (71% protection), when compared with the reference standard, chlorpheniramine maleate (71% protection). Compounds II and VII showed negligible sedation (5% and 8% respectively) when compared with chlorpheniramine maleate (25%). Compounds II and VII could serve as prototype molecules for further development as a new class of H1-antihistamines.     

Synthesis and biological properties of 1-(4-substituted phenyl)-1-alkyl(aryl)-2-phenyl-3-piperidinopropan-1-ols

Interaction of α-phenyl-β-piperidino-4-substituted propiophenones with Grignard reagents in ether was used to synthesize 1-(4-substituted phenyl)-1-alkyl(aryl)-2-phenyl-3-piperidinopropan-1-ols. The antibacterial and antioxidant properties of the aminopropanol hydrochlorides were studied. Some of these compounds (3-(4-ethoxyphenyl)-2-phenyl-1-piperidinoheptan-, 3-(4-ethoxyphenyl)-2-phenyl-1-piperidonooctan-, and 2-phenyl-1-piperidino-3-(4-propoxyphenyl)decan-3-ol hydrochlorides) had moderate antibacterial activity and some (3-(4-ethoxyphenyl)-2-phenyl-1-piperidinopentan- and 3-(4-ethoxyphenyl)-5-methyl-2-phenyl-1-piperidinohexan-3-ol hydrochlorides) had high antioxidant activity.     

Synthesis and hypolipidemic activity of novel 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives

A novel series of 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high-fat-diet-induced hyperlipidemia in rats. Some of these compounds showed significant antihyperlipidemic activity.     

3-取代三唑醇类化合物的合成及抗真菌活性

目的设计合成1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-烷氧基苯基哌嗪-2-丙醇和1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代硫醚-2-丙醇化合物,并进行体外抗真菌活性测试.方法以间二氟苯为起始原料,经多步反应,得到中间体环氧化物甲烷磺酸盐,再与各种烷氧基苯基哌嗪和取代硫醇开环得到目标化合物,按国际标准抗真菌敏感性实验方法测定其体外抗真菌活性.结果共合成12个(其中11个为新化合物)目标化合物,经元素分析,1H-NMR和IR确证结构,其中4个化合物的抗真菌活性强于对照品氟康唑和酮康唑.结论含烷氧苯基哌嗪侧链的三唑醇类化合物具有较强的抗真菌活性.     

Synthesis and pharmacological activity of 1-(4-substituted phenyl)-1-alkyl(aryl)-3-piperidinopropanol hydrochlorides

Aminomethylation of substituted acetophenones with paraformaldehyde and piperidine hydrochloride yielded 4-substituted β-piperidinopropiophenones. Interaction of compounds I with the Grignard reagents in ether yielded 1-(4-substituted phenyl)-1-alkyl(aryl)-3-piperidinopropanols. The anti-inflammatory, analgesic, antipyretic, central m-cholinoblocking, and peripheral n-cholinoblocking actions of 1-(4-substituted phenyl)-1-alkyl(aryl)-3-piperidinopropanol hydrochlorides were studied. The study compounds were found to have marked central m-cholinoblocking and peripheral n-cholinoblocking activities. Only 1-(4-methoxyphenyl)-1-cyclohexyl-3-piperidinopropanol hydrochloride had 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.     

Synthesis and antimicrobial evaluation of some 3-(substituted phenacyl)-5-[4'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4- thiazolidinediones.

Synthesis and in vitro antimicrobial activity of some 3-(substituted phenacyl)-5-[4'(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2-4- thiazolidinedione derivatives are described. These products were synthesized by the Knoevenagel reaction from 4'-flavone carboxaldehyde and 3-substituted phenacyl-2,4-thiazolidinediones.     

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. II. Synthesis of new series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines and related compounds with potential CNS activity

New series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines have been prepared. The 1-substituted products were obtained starting from 3-hydrazino-2H-1,4-benzothiazine derivatives (III) by treatment with chloroacethyl chloride followed by cyclization of the resulting chloroacethylderivatives into the chloromethyltriazolobenzothiazines (IV a-e), which were then reacted with the appropriate amines to give the desired compounds (V a-n). Other 1-substituted compounds were prepared by ring closure of (III) with cyanogen bromide, affording 1-amino-4H-s-triazolo [3,4-c]-1,4-benzothiazines (XI a-e). The 2-substituted compounds (VIII) were prepared from 2,4-dihydro-1H-s-triazolo [3,4-c]-1,4-benzothiazin-1-ones (VII), synthesized from (I) by reaction with ethyl carbazate. The aminoalkyl side chain was introduced into (VII) in two steps: first by treatment with 1-bromo-3-chloropropane, then by refluxing the resulting product with the appropriate amine. Some 4H-tetrazolo[5,1-c]-1,4-benzothiazines (XII) were also synthesized from (III). Preliminary pharmacological data on the CNS activity of the synthesized tricyclic compounds are reported.     

Synthesis of 2-(4-substituted phenyl)-3-[4-substituted piperazino(piperidino)]propan-1-ol dihydrochlorides and their effects on adenosine deaminase activity

Aminomethylation of 4-substituted acetophenones yielded a series of β-amino-4-substituted propiophenones. Reduction of these with lithium alumohydride in dry ether produced 1-(4-substituted phenyl)-3-[4-substituted piperazino(piperidino)]propan-1-ols, which were then converted to the corresponding dihydrochlorides. The abilities of these compounds to inhibit adenosine deaminase, a key enzyme in purine metabolism in living organisms, were studied. Some of the compounds had quite marked inhibitory effects on the enzyme. The abilities of the compounds synthesized here to inhibit adenosine deaminase were found to depend on their structure. It is of note that virtually all the compounds inhibited the high molecular weight form of the enzyme to a significantly lesser extent than the low molecular weight form.     

Synthesis of some new diaryl and triaryl hydrazone derivatives as possible estrogen receptor modulators

1,2-Bis(4-substituted phenyl)-2-methyl ethanone (2,4-dinitrophenyl)hydrazones and 1-naphthyl-1-(4-substituted phenyl)-methanone (2,4-dinitrophenyl)hydrazones have been synthesized and evaluated for their anti-implantation, uterotrophic, antiuterotrophic, anticancer and antimicrobial activities. Diphenolic hydrazone (compound 6) showed maximum uterotrophic inhibition of 70%, whereas compound 20 exhibited cytotoxicity in the range of 50-70% against MCF-7 and ZR-75-1 human malignant breast cell lines.     

Synthesis, antitubercular, antifungal and antibacterial activities of 6-substituted phenyl-2-(3'-substituted phenyl pyridazin-6'-yl)-2,3,4,5-tetrahydropyridazin-3-one

A series of 6-substituted phenyl-2-(3'-substituted phenyl pyridazin-6'-yl)-2,3,4,5-tetrahydropyridazin-3-ones has been synthesized. An appropriate aromatic hydrocarbon reacts with succinic anhydride in presence of AlCl3 to yield beta-aroyl propionic acid. The corresponding acid was cyclized with hydrazine hydrate to give 6-(substituted aryl)-2,3,4,5-tetrahydro-3-pyridazinone, which was heated on steam bath with phosphorus(V) oxychloride to yield 3-chloro 6-substituted phenyl pyridazine. This intermediate after reaction with hydrazine hydrate was converted into 3-hydrazino-6-substituted phenyl pyridazine. The resulting product was converted into 6-substituted phenyl-2-(3'-substituted phenyl pyridazin-6'-yl)-2,3,4,5-tetrahydropyridazin-3-one by reacting with substituted aroyl propionic acid. Spectral data (IR, NMR, mass spectra) confirmed the structures of the synthesized compounds. The synthesized compounds were investigated for their in vitro antitubercular, antifungal and antibacterial activities. The results indicated that the synthesized compounds have mild to potent activities with reference to their appropriate reference standards.     

Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914)

A series of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones was synthesized and evaluated for positive inotropic activity. Only compounds with two small alkyl groups at C-4 showed significant activity. The structure-activity relationships for optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The phosphodiesterase inhibitory activity is also reported and correlated with the substitution pattern at C-4 in the pyrazolone ring.