Small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26): synthesis and biological evaluation of imidazole methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates

The synthesis and potent inhibitory activity of novel imidazole methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates in a MCF-7 CYP26A1 microsomal assay is described. The induction of CYP26A1 mRNA was used to evaluate the ability of the compounds to enhance the biological effects of all-trans retinoic acid (ATRA) in a retinoid-responsive neuroblastoma cell line. The most promising inhibitor, 3-imidazol-1-yl-2-methyl-3-[4-(naphthalen-2-ylamino)-phenyl]-propionic acid methyl ester (20), with an IC(50) of 3 nM (compared with liarozole IC(50) of 540 nM and R116010 IC(50) of 10 nM) was further evaluated for CYP selectivity using a panel of CYP enzymes, mutagenicity (Ames screen), and hepatic stability.     

Synthesis and biological studies of a novel series of 4-(4-(1H-imidazol-1-yl)phenyl)-6-arylpyrimidin-2-amines

A novel series of eleven 4-(4-(1H-imidazol-1-yl)phenyl)-6-arylpyrimidin-2-amines has been prepared from synthesized 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones and evaluated for phosphodiesterase (PDE) inhibition and antimicrobial activities. N-arylation of imidazole with 4-fluorobenzaldehyde using hexadecyltrimethylammonium bromide as catalyst gave 4-(1H-imidazol-1-yl) benzaldehyde which on treatment with substituted acetophenones yielded corresponding chalcones (1a–1k). Each chalcone on further reaction with guanidine hydrochloride resulted in title compounds (2a–2k). Pyrimidines thus synthesized were subjected to biological studies. Some compounds showed marked activities in PDE inhibition and anti-bacterial and anti-fungal bioassays.     

Anticonvulsant properties of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methyl-piperazin-1-yl)propyl] derivatives of 3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione

Two series of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methylpiperazin-1-yl)-propyl]-3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione derivatives were synthesized and tested for anticonvulsant activity in the maximum electroshock (MES) seizure and pentetrazole (sc PTZ) seizure threshold tests. Compounds with an aromatic ring at position-3 of pyrrolidine-2,5-dione exhibited anticonvulsant activity in the MES test. For that series of compounds, ED50 values were determined. The most potent in the series were derivatives and with a chlorine atom at position-3 or 4 of the aromatic ring. Those compounds exhibited strong anticonvulsant activity, and their ED50 values ranged from 29 to 48 mg/kg. Introduction of the spirocycloalkyl ring into the position-3 of pyrrolidine-2,5-dione made those compounds inactive.     

Synthesis of 2-[4,5-dimethyl-1-(phenylamino)-1H-imidazol-2-ylthio]-N-(thiazole-2-yl)acetamide derivatives and their anticancer activities

In this work, 2-(4,5-dimethyl-1-(phenylamino)-1H-imidazol-2-ylthio)-N-(thiazol-2-yl) acetamide derivatives were synthesized by reacting 4,5-dimethyl-1-(phenylamino)-1H-imidazole-2(3H)-thione derivatives with some 2-chloro-N-(thiazol-2-yl)acetamide compounds. The structure of synthesized compounds was confirmed by IR, ¹H NMR, and mass spectra. Anticancer activities of the compounds selected by the National Cancer Institute were investigated by testing against a panel of 60 different human tumor cell lines derived from nine neoplastic cancer types. Compounds 7, 13, and 23 exhibited reasonable anticancer activity against the screened cancer types with relatively low GI₅₀ values. The compounds showed high activity against melanoma-type cell lines.     

Synthesis and antileukemic activity of novel 4-(3-(piperidin-4-yl) propyl)piperidine derivatives

To explore the anticancer effect associated with the piperidine framework, several (substituted phenyl) {4-[3-(piperidin-4-yl)propyl]piperidin-1-yl} methanone derivatives 3(a-i) were synthesized. Variation in the functional group at N-terminal of the piperidine led to a set of compounds bearing amide moiety. Their chemical structures were confirmed by (1) H NMR, IR and mass spectra analysis. Among these, compounds 3a, 3d and 3e were endowed with antiproliferative activity. The most active compound among this series was 3a with nitro and fluoro substitution on the phenyl ring of aryl carboxamide moiety, which inhibited the growth of human leukemia cells (K562 and Reh) at low concentration. Comparison with other derivative (3h) results shown by LDH assay, cell cycle analysis and DNA fragmentation suggested that 3a is more potent to induce apoptosis.     

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).     

5-三氟甲基-3-(4-甲基-1H-咪唑-1-基)苯胺的合成

3,5-二硝基三氟甲苯(2)与氟化四甲铵进行氟代反应,所得单氟中间体再与4-甲基-1H-咪唑进行取代反应得到5-三氟甲基-3-(4-甲基-1H-咪唑-1-基)-硝基苯(3),然后在Pd/C催化下氢化还原制得抗肿瘤药尼罗替尼的中间体5-三氟甲基-3-(4-甲基-1H-眯唑-1-基)-苯胺(1),总收率约50％(以2计).     

Evidence of Polymorphism on the Antitrypanosomal Naphthoquinone (4E)-2-(1H-Pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one

The aim of this study was to characterize the solid state properties of (4E)-2-(1H-pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one (BiPNQ), a compound with a significant inhibitory activity against Trypanosoma cruzi, the etiological agent of Chagas disease (American trypanosomiasis). Methods used included Differential Scanning Calorimetry (DSC), Thermogravimetry (TG), Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD), Hot Stage, and Confocal Microscopy. Two BiPNQ samples were obtained by crystallization from absolute methanol and 2-propanol-water that exhibited different thermal behaviours, PXRD patterns, and FTIR spectra, indicating the existence of an anhydrous form (BiPNQ-I) and a solvate (BIPNQ-s), which on heating desolvated leading to the anhydrous modification BiPNQ-I. It was determined that FTIR, DSC, and PXRD are useful techniques for the characterization and identification of the crystalline modifications of BiPNQ.     

4-(tetralin-1-yl)- and 4-(naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as sigma receptor ligands with agonist sigma2 activity

Several 1-cyclohexylpiperazine derivatives related to sigma(2) receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (33, K(i) = 0.34 nM) were synthesized and tested in radioligand binding assays, to attempt a structure-affinity relationship study. Intermediate alkyl chain length and methoxyl group position on the tetralin nucleus were varied. A few naphthalene analogues were also prepared. High affinities were found in sigma(2) receptor binding for almost all compounds, some of which displayed K(i) values in subnanomolar range, but low sigma(2)/sigma(1) selectivities were found. The highest sigma(2) affinities were displayed by compounds with an intermediate alkyl chain of three (32 and 43) or five methylenes (39 and 46). Quite high sigma(1) receptor affinity was found for compounds with a four-methylene chain; 36 (K(i) = 0.036 nM) and 45 (K(i) = 0.22 nM) displaying good sigma(1)/sigma(2) selectivity (406- and 139-fold, respectively). Moreover, homologues of compound 33 displayed also satisfactory selectivities over dopamine D(2)-like, serotonin 5-HT(3), and adrenergic alpha(1) receptors. These compounds and a few others were tested in the inhibition of the electrically evoked contractions in guinea pig bladder and were demonstrated to be full sigma(2) agonists. The activity values correlated well to the affinity scale (EC(50) in microM range). 33 and related compounds are proposed as a class of potential antineoplastic and PET diagnosis agents.     

Thromboxane synthase inhibitors. Synthesis and pharmacological activity of (R)-, (S)-, and (+/-)-2,2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)- methoxy]methyl]ethoxy]hexanoic acids

A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.     

咪苯嗪酮对花生四烯酸诱导的大鼠脑血栓形成的影响

花生四烯酸(AA)0.25～1 mg·kg~(-1)经颈内动脉注射能诱发大鼠同侧大脑半球脑内血栓形成,明显增加伊文思蓝通过血脑屏障渗入脑实质的量,峰值为205±s 50 mg·kg~1脑组织,相应对照组为10±s 5mg·kg~1,咪苯嗪酮0.25～0.5mg·kg~1 iv能对抗AA引起的大鼠脑血栓形成,显著降低脑实质内伊文思蓝的含量,作用呈剂量依赖性,且强于哒唑氧苯     

Cardiotonic agents. 7. Prodrug derivatives of 4-ethyl-1,3-dihydro- 5-[4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H-imidazol-2-one.

The cardiotonic agent 4-ethyl-1,3-dihydro-5-4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H- imidazol-2-one (1) was found to have low bioavailability when administered orally to rats and dogs. A series of N-acyl derivatives, an underutilized prodrug of acidic NH compounds, has been synthesized and tested for their ability to improve the oral bioavailability of 1. Reaction of the monosodium salt of 1 with various anhydrides afforded the N-1 monoacylimidazolones with surprisingly high regioselectivity. In addition to the prodrugs, acylation of 1 with propionic or phenylacetic anhydride led to the novel 3H-pyrrolo[1,2-c]imidazole-3,5(2H)-diones 6. The prodrugs showed a significant increase in the partition coefficients with a minor decrease in the aqueous solubility. The benzoyl derivative 4b exhibited the highest stability in both pH 1.5 and 7.4 buffer solutions. Further evaluation of 4b showed rapid conversion to 1 in canine plasma (t1/2 = 38 min), and human plasma (t1/2 = 10 min). Oral studies indicated that the bioavailability of 4b was increased to greater than 75% (compared to less than 20% for 1), and hemodynamic studies demonstrated that the selective inotropic profile of 1 was retained.     

4-[4-(3,4-亚甲二氧基苯基)-5-(2-吡啶基)-1H咪唑-2-基]苯甲酰胺的合成工艺改进

目的改进4-[4-(3,4-亚甲二氧基苯基)-5-(2-吡啶基)-1H-咪唑-2-基]苯甲酰胺(SB-431542)的合成工艺.方法关键中间体4-[4-(3,4-亚甲二氧基苯基)-5-(2-吡啶基)-N-1-羟基咪唑-2-基]苯腈(1)以三氯化肽[Ti(Ⅲ)Cl3]还原得到4-[4-(3,4-亚甲二氧基苯基)-5-(2-吡啶基)-1H-咪唑-2-基]苯腈(2);2在叔丁醇中以氢氧化钾水解将腈基转化为胺酰基得到了SB-431542.结果与讨论中间体和终产物经1H-NMR和MS鉴定,均与文献的数据相符.该合成工艺缩短了合成路线、简化了操作、提高了收率和纯度,避免了使用毒性大的亚磷酸三乙酯[P(OEt)3].     

Syntheses and biological activities of 3-[4-(alkoxycarbonyl)phenyl]sydnones and their derivatives

Four new 3-[4-(alkoxycarbonyl)phenyl]sydnones have been synthesised. The hydrazide 4 is condensed with various aromatic aldehydes to obtain the corresponding Schiff bases. Antimicrobial activities of the sydnones and some Schiff bases are reported. Mass spectral fragmentation of 3[4-(ethoxycarbonyl)phenyl]sydnone is discussed.     

Syntheses of 1-Aryl-2-{4-[4-(3-oxobutyl)phenyl]piperazin-1-yl}ethanones

Syntheses of the biologically active N¹-[4-(3-oxobutyl)phenyl]-N⁴-phenacylpiperazines 1a-g from N-phenylpiperazine (2) are described.