Synthesis and QSAR studies of novel 1-substituted-2-aminobenzimidazoles derivatives

A series of novel 1-substituted-2-aminobenzimidazole derivatives were synthesized. The structures of the synthesized compounds were confirmed by 1H-NMR spectra and by elemental analysis. Acute toxicities of these compounds were detected on mice via toxicity (logLD50). QSAR analysis of these chemicals was studied on the relationship between acute toxicity and the octanol/water partition coefficient (LogP). The products were identified by the results of elemental analysis and 1H-NMR spectra. The toxicity (logLD50) of 2-aminobenzimidazole 1-substituents were correlated well with the partition coefficient LogP, r=0.9243. The bioactivity (toxicity) of 2-aminobenzimidazoles can be predicted by the molecular structural parameter such as LogP.     

Role of erythropoietin in brain homeostasis, neurodevelopment and neuroprotection

Erythropoietin is known as a cytokine regulating the erythrocyte production. Based on recent research it became clear that it is secreted not only by the kidney, but by the central nervous system as well, and erythropoietin receptors are present there, too. Animal and human studies found that the expression of erythropoietin and its receptor is changing through neurodevelopment, which has impact on the differentiation of neuronal cells and is essential for normal neurodevelopment. In addition erythropoietin is protective against several mechanisms of neuronal injury: it alleviates the outcome of hypoxia and glutamate toxicity and has antiapoptotic effects. Based on these results the neuroprotective effects of exogenously administered erythropoietin was studied in several clinical studies. The available data indicate that erythropoietin or its analogues may have a role in neuroprotection in clinical settings.     

The synthesis of N-phenoxyethyl-1-substituted-1,2,3,4-tetrahydroisoquinolines and their alpha1-adrenoceptor blocking activity

A series of phenoxyisoquinolines, N-phenoxyethyl-1-(2-nitrophenyl)-1,2,3,4-THIQs 3a-3d, N-phenoxyethyl-1-benzyl-1,2,3,4-THIQ 3e, N-phenoxyethyl-1-(2-aminophenyl)-1,2,3,4-THIQs 5f-5i, N-phenoxyethyl-1-(2-phenoxyethylaminophenyl)-1,2,3,4-THIQs 5f'-5i', have been synthesized and tested in isolated rat vas deferens alpha-adrenoreceptors. Comparison of pA2 values for these compounds in the presence of phenylephrine confirms that alpha(1)-adrenoceptor blocking activity of 3a-3d (-NO(2) series) is more active than 6a-6c (-NH(2) series) in the aortic rings isolated from SD rats. On the other hand, the electron-donating group at the 6-position of isoquinoline ring either increases or decreases the alpha(1)-adrenoceptor blocking activity.     

Synthesis, antimicrobial, and anti-inflammatory activities of novel 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles and 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazoles

Reaction of 1-adamantanecarbonyl chloride with certain carboxylic acid hydrazides in pyridine yielded the corresponding N-acyl adamantane-1-carbohydrazide derivatives 3a-j, which were cyclized to the corresponding 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles 4a-j via heating with phosphorus oxychloride. Treatment of 1-adamantylisothiocyanate with some carboxylic acid hydrazides in ethanol yielded the corresponding 1-acyl-4-(1-adamantyl)-3-thiosemicarbazides 7a-g, which were cyclized to the corresponding 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazole derivatives 8a-g. Compounds 4a-j, 7a-g, and 8a-g were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or moderate activities particularly against the tested Gram-positive bacteria Bacillus subtilis. Meanwhile, compounds 4i and 8g displayed marked antifungal activity against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenin-induced paw oedema method in rats. The oxadiazole derivatives 4c, 4g, 4i and 4j produced good dose-dependent anti-inflammatory activity.     

Synthesis and in vitro leishmanicidal activity of 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-substituted-1,3,4-thiadiazole derivatives

A series of 2-(1-methyl-5-nitroimidazol-2-yl)-5-(1-piperazinyl, 1-piperidinyl and 1-morpholinyl)-1,3,4–thiadiazoles (3a–g) were synthesized and evaluated for in vitro leishmanicidal activity against Leishmania major promastigotes. The leishmanicidal data revealed that compounds 3a–g had strong and much better leishmanicidal activity than the reference drug pentostam. Compound 3c (piperazine analog) was the most active compound (IC₅₀ = 0.19 μM).     

Synthesis and DHFR inhibitory activity of a series of 6-substituted-2,4-diaminothieno[2,3-d]pyrimidines

A series of 6-aralkyl substituted 2,4-diaminothieno[2,3-d]pyrimidines in which the 6-aryl group is separated from the thieno[2,3-d]pyrimidine ring by two to five methylene groups were synthesized and studied as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. Compounds in which the thieno[2,3-d]pyrimidine ring is separated from the 6-aryl substituent by three methylene groups were the most potent inhibitors of the series (with IC(50) values ranging from 0.24 and 11.0 microM) but those with two methylene groups between the aromatic rings were the most selective agents.     

Synthesis and structure-activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors

A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing a 1,2,5-triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC₅₀ = 4.64 μM), a letrozole 1 analogue bearing para-cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen.     

A facile, one-pot synthesis, characterization and antimicrobial activity of o-hydroxy anilide derivatives and 1-substituted-1,3-dicyclohexylurea analogs of long chain carboxylic acids

A series of novel o-hydroxy anilide derivatives and 1-substituted-1,3-dicyclohexylurea analogs of long chain carboxylic acids have been synthesized. The structures of the synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR and mass spectral data. All the synthesized compounds were tested for their antimicrobial activity by disk diffusion assay with slight modifications against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. After that minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs) and minimum fungicidal concentrations (MFCs) of all the synthesized compounds were determined. The investigation of antimicrobial screening data revealed that all the tested compounds showed moderate to good microbial inhibitions. Compounds 3e, 4e, 3f and 4f were found to be the most potent antimicrobial agents.     

Synthesis and cytotoxic activity of 2-acyl-1H-indole-4,7-diones on human cancer cell lines

Synthesis and cytotoxic activity of a series of 2-acyl-1H-indole-4,7-diones on human cancer cell lines are described. Due to close structural relationship to 2-acylindoles, potent inhibitors of tubulin polymerization, the mode of action of these novel compounds has been investigated. Cytotoxicity, the influence on tubulin polymerization, and cell cycle dependent cytotoxicity on colon carcinoma cells by investigation of RKO exo p27 versus RKO p27(kip1) cells are described. IC50 values of arrested versus proliferating cells differ only in a range of two to fourfold and therefore cellular targets, predominantly relevant for mitotic progression, are excluded. As shown by the significant difference in the IC90 values on different tumor cell lines, the investigated compounds seem to act selectively on mammary and renal cancer cells.     

Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines

In order to explore the antiproliferative effect associated with the piperazine framework, several 1-benzhydrylpiperazine derivatives 8(a-d), 9(a-d) and 10(a-h) were synthesized. Variation in the functional group at N-terminal of the piperazine led to three sets of compounds, bearing the sulfonyl, amide and thiourea, respectively. Their chemical structures were confirmed by (1)H NMR, LCMS, IR and elemental analysis. The antiproliferative effect of the compounds were evaluated in vitro using the MTT colorimetric method against one normal cell line (NF-103 skin fibroblast cells) and four human cancer cell lines (MCF-7 breast carcinoma cell line, HepG-2 hepatocellular carcinoma cell line, HeLa cervix carcinoma cell line and HT-29 colon carcinoma cell line) for the time period of 24 h. Among the series, four compounds exhibited interesting growth inhibitory effects against all four cell lines.     

Synthesis, biological activity and molecular modeling studies of novel COX-1 inhibitors

Synthesis of new potential COX-1 and/or COX-2 inhibitors, derivatives of 1,1-di-(3-carboxyphenyl)ethane, their biological activity, docking results on COX-1 enzyme and absorption, distribution, metabolism, excretion (ADME) properties are presented. In addition to known interactions between ketoprofen and ibuprofen, leading NSAID agents and COX-1 active site, the possibility of formation of additional interactions is explored. Interactions with Ala527, and with one of the water molecules situated within the active site are identified. Molecular mechanics and DFT calculations for studied compounds have revealed free rotation around two central bonds (C1-C3' and C1-C3"), making them flexible, thus easier to enter and adjust to the active site. Further modifications of core structure have been undertaken to optimize biological activity and ADME properties. As a result, two of the compounds are indicated as novel COX-1 inhibitors.     

Synthesis of 3-substituted-2-oxoindole analogues and their evaluation as kinase inhibitors, anticancer and antiangiogenic agents

Several analogues of the 3-substituted-2-oxoindole chemotype were synthesized by condensing isatin or the appropriate haloisatin with some amino acids or histamine under neutral conditions. All the imino derivatives produced were tested for kinase inhibitory properties against three serine/threonine kinases, namely CDK1/cyclin B, CDK5/p25 and GSK3alpha/beta. Most of the histidine derivatives showed inhibitory properties to the three kinases in the low micromolar range. The histamine derivatives were less potent against CDK1/cyclin B and CDK5/p25 and totally inactive against GSK3alpha/beta. So, the management of the carboxyl function may be a tool to impart selectivity in such family of kinases. Docking of 2-[[-5-bromo-2-oxoindolin-3-ylidene]amino]-3-(1H-imidazol2-yl)propanoic acid 14 to CDK5/p25 indicates that this compound can interact with the enzyme through four hydrogen bonds; for GSK/3beta, the ligand poses itself in another orientation, also four hydrogen bonds can be formed between the ligand and the receptor, otherwise hydrophobic interactions seem to predominate. Also, all the final compounds were tested for their in vitro antitumor properties against MCF7 (breast), NCI-H460 (lung) and SF268 (CNS) cancer cell lines. None of the synthesized compounds was cytotoxic at 10(-4) molar concentration. Moreover, compounds 13 and 14 were tested for potential antiangiogenic properties by testing their ability to inhibit the proliferation of human umbilical vein endothelial cells (HUVECs), cord formation and migration in response to chemoattractant. Only compound 14 showed moderate inhibitory properties to HUVECs proliferation and cord formation while its non-brominated derivative 13 did not. Thus, the antiangiogenesis properties are not apparently caused by inhibition of any of the tested kinases.     

Synthesis, anti-mycobacterial, anti-trichomonas and anti-candida in vitro activities of 2-substituted-6,7-difluoro-3-methylquinoxaline 1,4-dioxides

A new series of 23 6,7-difluoro-3-methyl-2-phenylthio/phenylsulfonyl/phenylsulfinyl/benzylamino/phenylamino-quinoxaline 1,4-dioxides variously substituted in the phenyl moiety, was synthesized and submitted to in vitro evaluation for anti-mycobacterial, anti-trichomonas, anti-candida, anti-mycoplasma and antibacterial activities. In anti-mycobacterial assays, several compounds resulted active (MIC90 = 2.0-4.0 microg/ml) against Mycobacterium tuberculosis H37Rv. Anti-trichomonas screening showed a generally good activity of all compounds (MBC = 0.39-25.0 microg/ml) versus Trichomonas vaginalis, in particular the derivatives 5a,d, 7a, 9 and 11c ranged 0.39-0.78 microg/ml (metronidazole MBC = 12.5 microg/ml). Results of anti-candida assays showed that derivatives 7a, 8a,d and 9 were active against several species of Candida (C. albicans, C. krusei, C. parapsilosis and C. glabrata), having MIC50 between 3.9 and 31.25 microg/ml. The latter compounds were also submitted to anti-mycoplasma assay against Mycoplasma hominis, the results obtained showed that 7a, 8a,d and 9 inhibited the growth of the mycoplasma at the concentration of 0.1 mg/ml. In antibacterial tests only a few compounds showed an MIC50 lower than 62.5 microg/ml against representative strains of Gram-positive and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Vibrio alginolyticus and Pseudomonas aeruginosa).     

Heterocyclic quinones VIII. Synthesis and anti-neoplastic evaluation of 7-substituted-1H-pyrrolo[3,2-c]quinoline-6,9-diones and 3-substituted-11H-indolo[3,2-c]quinoline-1,4-diones

7-Methoxy-2,3,4-trimethyl-1H-pyrrolo[3,2-c]quinoline-6,9-dione 13 and 3-methoxy-6-methyl-11H-indolo-[3,2-c]quinoline-1,4-diones 15 and 19 were obtained by oxidation of quinolinamines 9, 11 and 12 with Fremy's salt. The synthesis method of amines 9 and 11 consists of creating the pyrrole or indole nucleus according to Fisher's indolic reaction applied to hydrazones 8 and 10. Aromatization of 11 yielded quinolinamine 12. The nucleophilic substitution of methoxy by aziridine leads to quinones 14, 16 and 20. These quinones are highly cytotoxic for L1210 cells, but no activity could be established for the P388 lymphocytic leukemia in vivo.     

Synthesis and antiproliferative activity of 3-amino-N-phenyl-1H-indazole-1-carboxamides

A series of new 3-amino-N-phenyl-1H-indazole-1-carboxamides 10 have been prepared from commercially available phenyl isocyanate precursors 8 and 3-aminoindazole 9. Some of the synthesized compounds were evaluated for their in vitro antineoplastic activity against 60 human cell lines derived from seven clinically isolated cancer types (lung, colon, melanoma, renal, ovarian, brain, and leukemia) according to the NCI standard protocol. The test results indicated that 3-amino-1H-indazole-1-carboxamides 10 were endowed with an interesting antiproliferative activity. The most active compounds of this series, 10d,e, were able to inhibit cell growth of many neoplastic cell lines at concentrations lower than 1 microM (0.0153 microM in SR leukemia) causing a block in G0-G1 phase of cell cycle. Analysis of pRb expression showed that these two compounds increased the ratio between underphosphorylated pRb and total pRb. The X-ray structure of 10w, confirmed the 3-amino-N-phenyl-1H-indazole-1-carboxamide structure of compounds 10.     

Pharmacological evaluation of some new 1-substituted-4-hydroxy-phthalazines

In the present study, a series of 1-substituted-4-hydroxyphthalazines were synthesized and characterized by IR, 1H-NMR and Elemental analysis. The compounds were assayed against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The decrease in the elevated motor activity by introceptive chemical stimuli (amphetamine antagonistic activity) was studied at the dose level of 25 and 50 mg kg(-1) and cardiac activity was also studied. All the compounds exhibited significant anticonvulsant activity. Compounds 4, 12, 13 and 17 were most active of the seriesagainst MES-induced seizures. Compounds 2, 4, 13 and 17 exhibited significant decrease in the elevated motor activity at the dose of 50 mg kg(-1). Remarkable sympathetic blocking activity was observed with 3, 5, 6, 7, 9 and 15 only.     

红细胞生成素对缺氧缺血性脑损伤的神经保护作用研究进展

红细胞生成素是一种含有 16 5个氨基酸残基的唾液酸糖蛋白分子 ,过去一直认为它主要由肾脏和胎儿肝脏产生 ,是促进红系祖细胞增殖、分化与成熟的主要造血因子。近年来越来越多的研究表明 ,红细胞生成素具有神经活性 ,红细胞生成素及其受体在人类和啮齿类动物脑组织中广泛表达 ,缺氧缺血性脑损伤时表达显著增加 ,对缺氧缺血性损伤大脑发挥神经保护作用     

Prenylated derivatives of baicalein and 3,7-dihydroxyflavone: synthesis and study of their effects on tumor cell lines growth, cell cycle and apoptosis

Fourteen baicalein and 3,7-dihydroxyflavone derivatives were synthesized and evaluated for their inhibitory activity against the in vitro growth of three human tumor cell lines. The synthetic approaches were based on the reaction with prenyl or geranyl bromide in alkaline medium, followed by cyclization of the respective monoprenylated derivative. Dihydropyranoflavonoids were also obtained by one-pot synthesis, using Montmorillonite K10 clay as catalyst combined with microwave irradiation. In vitro screening of the compounds for cell growth inhibitory activity revealed that the presence of one geranyl group was associated with a remarkable increase in the inhibitory activity. Moreover, for the 3,7-dihydroxyflavone derivatives a marked increase in growth inhibitory effect was also observed for compounds with furan and pyran fused rings. The most active compounds were also studied regarding their effect on cell cycle profile and induction of apoptosis. Overall the results point to the relevant role of the prenylation of flavone scaffold in the growth inhibitory activity of cancer cells.