Bleaching activity of 4-phenyl-3-(substituted benzylthio)-4H-1,2,4-triazoles

A variety of 4-aryl- and 4-alkyl-3-(substituted benzylthio)-4H-1,2,4-triazoles were prepared and evaluated for their bleaching activity by the lettuce seedling test. Among the series of tested compounds, 4-(3-fluorophenyl)-3-(4-trifluoromethylbenzylthio)-4H-1,2,4-triazole (39) exhibited the highest bleaching activity, causing complete bleaching symptoms at 10 microM. In the dark condition, compound 39 inhibited the formation of such carotenoids as beta-carotene, violaxanthin, neoxanthin and lutein, resulting in the formation of zeta-carotene, phytoene, phytofluene and beta-zeacarotene, which were not detected in the untreated control. Treatment by compound 39 at 50 microM resulted in the amount of accumulated zeta-carotene being seven-fold higher than that of phytoene, phytofluene and beta-zeacarotene. These results suggest that compound 39 might have interfered with desaturation, especially zeta-carotene desaturation, during carotenoid biosynthesis.     

Design, synthesis, and biological evaluation of substituted 3-alkylthio-4,5-diaryl-4H-1,2,4-triazoles as selective COX-2 inhibitors

A new type of 4,5-diaryl-4H-1,2,4-triazole, possessing C-3 thio and alkylthio (SH, SMe or SEt) substituents, was designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo anti-inflammatory activity. The compound, 3-ethylthio-5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-4H-1,2,4-triazole (10d), exhibited a high in vitro selectivity (COX-1 IC50=20.5 nM; COX-2 IC50=1.8 nM; SI=11.39) relative to the reference drug celecoxib (COX-1 IC50=3.7 nM; COX-2 IC50=2.2 nM; SI=1.68) and also showed good anti-inflammatory activity compared to celecoxib in a carrageenan-induced rat paw edema assay.     

3-Thio-1,2,4-triazoles, novel somatostatin sst2/sst5 agonists

Novel 3-thio-1,2,4-triazoles have been obtained via a solution-phase parallel synthesis strategy, affording potent non-peptidic human somatostatin receptor subtypes 2 and 5 agonists.     

Synthesis of 1,2,4-triazole-linked urea/thiourea conjugates as cytotoxic and apoptosis inducing agents

A new series of 1,2,4-triazole-linked urea and thiourea conjugates have been synthesized and evaluated for their in vitro cytotoxicity against selected human cancer cell lines namely, breast (MCF-7, MDA-MB-231), lung (A549) prostate (DU145) and one mouse melanoma (B16-F10) cell line and compared with reference drug. The compound 5t showed significant cytotoxicity on MCF-7 breast cancer cell line with a IC₅₀ value of 7.22?±?0.47?µM among all the tested compounds. Notably, induction of apoptosis by compound 5t on MCF-7 cells was evaluated using different staining techniques such as acridine orange/ethidium bromide (AO/EB), annexin V-FITC/PI, and DAPI. Further, clonogenic assay indicates the inhibition of colony formation on MCF-7 cells by compound 5t. Moreover, the flow-cytometric analysis also revealed that compound 5t caused the arrest of cells at G0/G1 phase of cell cycle. In addition, the compounds when tested on normal human cells (L-132) were found to be safer with low cytotoxicity profile.     

Synthesis and structure-activity relationships of 1,2,4-triazoles as a novel class of potent tubulin polymerization inhibitors

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.     

Synthesis and biological evaluation of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups as potential hypoglycemic agents

A novel class of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups were designed and synthesized. The target compounds were assayed for the effects on the insulin release of isolated rat pancreatic islets and the glucose transport in adipocytes of rats. Some of them exhibited high potency. Compound 10 also had potent antiplatelet activity and showed an excellent property to protect collagen–epinephrine-induced mice mortality as well as plasma glucose-lowering activity in vivo. The preliminary pharmacological profile of compound 10 showed that it might be useful in the treatment of diabetics with cardiovascular and nephropathy complications.     

Trisubstituted 1,2,4-triazoles as ligands for the ghrelin receptor: on the significance of the orientation and substitution at position 3

The synthesis and structure-activity relationships concerning 3,4,5-trisubstituted 1,2,4-triazoles as ghrelin receptor ligands are described. The importance of the starting aminoacid material as well as its configuration was explored and the (D) Trp residue was found to lead to the best agonist or antagonist compounds.     

Synthesis and antitumor activity of 1,2,4-triazoles having 1,4-benzodioxan fragment as a novel class of potent methionine aminopeptidase type II inhibitors

A series of 1,2,4-triazole derivatives containing 1,4-benzodioxan (5a-5q) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential MetAP2 inhibitors. All the synthesized compounds were first reported. Among the compounds, compound 5k showed the most potent biological activity against HEPG2 cancer cell line (IC(50)=0.81 μM for HEPG2 and IC(50)=0.93 μM for MetAP2), which was comparable to the positive control. Docking simulation by positioning compound 5k into the MetAP2 structure active site was performed to explore the possible binding model. The results of apoptosis and Western-blot assay demonstrated that compound 5k possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 5k with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell.     

Design,green synthesis and pharmacological evaluation of novel 5,6-diaryl-1,2,4-triazines bearing 3-morpholinoethylamine moiety as potential antithrombotic agents*

The aim of this research work was to investigate a series of novel 5,6-diaryl-1,2,4-triazines (3a–3q) containing 3-morpholinoethylamine side chain, and to address their antiplatelet activity by in vitro, ex vivo and in vivo methods. All compounds were synthesized by environment benign route and their structures were unambiguously confirmed by spectral data. Compounds (3l) and (3m) were confirmed by their single crystal X-ray structures. Out of all the synthesized compounds, 10 were found to be more potent in vitro than aspirin; six of them were found to be prominent in ex vivo assays and one compound (3d) was found to have the most promising antithrombotic profile in vivo. Moreover, compound (3d) demonstrated less ulcerogenicity in rats as compared to aspirin. The selectivity of the most promising compound (3d) for COX-1 and COX-2 enzymes was determined with the help of molecular docking studies and the results were correlated with the biological activity.     

Unsymmetrically substituted guanidines as potent histamine H3-receptor antagonists

Unsymmetrically trisubstituted and disubstituted guanidine derivatives of (1H-imidazol-4-yl)alkyl amines were synthesized and investigated for histamine H₃-receptor activity. Electron-withdrawing substitution of the guanidino group resulted in antagonists with a potential prodrug character. The H₃-receptor selective N¹-cyclohexylmethyl-N²-[3-(1H-imidazol-4-yl)propyl]guanidine possesses a -log K_i of 9.1.     

4-methyl-1,2,4-triazol-3-yl heterocycle as an alternative to the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA

Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA^™ series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure–activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.     

Chemiluminescence of bicyclic dioxetanes bearing a hydroxyphenyl moiety substituted with carbazolyl, indolyl or benzotriazolyl group in the coordination sphere.

Bicyclic dioxetanes bearing a 3-(carbazol-9-yl)-5-hydroxyphenyl 2a, 3-hydroxy-5-(indol-1-yl)phenyl 2b, or 3-(benzotriazol-1-yl)-5-hydroxyphenyl group 2c were synthesized. Base-induced decomposition of dioxetane 2a displayed intense light, the maximum wavelength (lambda(max) (CTICL)) of which changed depending on the crown ether complex of potassium t-butoxide used as a base, although the magnitude of lambda(max) (CTICL) change was considerably smaller than the case of dioxetane bearing a 3-(anthracen-9-yl)-5-hydroxyphenyl group 1. Chemiluminescence (CL) from 2b resembled closely that from 2a in response to the crown ether complexes. On the other hand, dioxetane 2c exhibited emission of red light on treatment with tetrabutylammonium fluoride. The colour of light changed significantly and exhibited two peaks in the CL spectrum when treated with complex of bulky dibenzyldiazacrown ether 13.     

Production of substituted catechols from substituted benzenes by a Pseudomonas sp.

In the presence of a halobenzene or benzonitrile, Pseudomonas T-12 can produce substituted catechols from the corresponding substituted benzenes. A variety of monosubstituted benzenes with substituents containing up to four carbons, and some meta- and para- disubstituted benzenes, can serve as catechol precursors.     

Synthesis and anticonvulsant evaluation of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines

A series of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazole derivatives was synthesized as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that 3-ethyl-4-(4-octyloxyphenyl)-4H-1,2,4-triazole 3q was found to be the most potent with ED(50) value of 8.3mg/kg and protective index (PI=TD(50)/ED(50)) value of 5.5, but compound 3r, 3-ethyl-4-(4-octyloxyphenyl)-4H-1,2,4-triazole, exhibited better PI value of 9.3, which was much greater than PI value of the prototype drug phenytoin. For explanation of the possible mechanism of action, the compound 3r was tested in pentylenetetrazole test, isoniazid test, thiosemicarbazide test, 3-mercaptopropionic acid and strychnine test.     

Design,modification and 3D QSAR studies of novel naphthalin-containing pyrazoline derivatives with/without thiourea skeleton as anticancer agents

Two series of novel naphthalin-containing pyrazoline derivatives C1–C14 and D1–D14 have been synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. Compound D14 displayed the most potent activity against EGFR and A549 cell line (IC₅₀ = 0.05 μM and GI₅₀ = 0.11 μM), being comparable with the positive control Erlotinib (IC₅₀ = 0.03 μM and GI₅₀ = 0.03 μM) and more potent than our previous compounds C0–A (IC₅₀ = 5.31 μM and GI₅₀ = 33.47 μM) and C0–B (IC₅₀ = 0.09 μM and GI₅₀ = 0.34 μM). Meanwhile, compound C14 displayed the most potent activity against HER-2 and MCF-7 cell line (IC₅₀ = 0.88 μM and GI₅₀ = 0.35 μM), being a little less potent than Erlotinib (IC₅₀ = 0.16 μM and GI₅₀ = 0.08 μM) but far more potent than C0–A (IC₅₀ = 6.58 μM and GI₅₀ = 27.62 μM) and C0–B (IC₅₀ = 2.77 μM and GI₅₀ = 3.79 μM). The docking simulation was performed to analyze the probable binding models and the QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future. The structural modification of introducing naphthalin moiety reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. Moreover, the replacement of thiourea skeleton by using benzene ring resulted in the slight diversity of the two series towards specific targets.     

Improving the selectivity of acyclic nucleoside analogues as inhibitors of human mitochondrial thymidine kinase: replacement of a triphenylmethoxy moiety with substituted amines and carboxamides

Two series of analogues of the novel human mitochondrial thymidine kinase inhibitor 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine were synthesized by replacing the triphenylmethoxy moiety by a variety of substituted amines and carboxamides. In all the cases, the selectivity against the mitochondrial enzyme was either maintained or improved, and several derivatives were almost as potent as the parent compound. A molecular model was built that can account for the observed selectivities.     

Some properties of a unique cadmium-binding moiety in the soluble fraction of rat testes.

A 30,000 molecular weight testicular Cd-binding peak (30,000 MW Cd-BP) previously implicated in Cd-induced testicular injury was unstable during storage with respect to apparent molecular weight determined by Sephadex G-75 chromatography. Storage of testicular cytosol labeled with 109Cd in vivo or in vitro for several days at 4 degrees C under nitrogen resulted in disappearance of the 30,000 MW Cd-BP and increased 109Cd uptake in other protein fractions. Rechromatography of the previously isolated 30,000 MW Cd-BP after storage gave rise to a 109Cd peak eluting in the higher molecular weight region. The latter effect was prevented by 1 mM dithiothreitol, suggesting that sulfhydryl groups were involved in the apparent aggregation. The 30,000 MW Cd-BP found in testes of rats was not present in testes of roosters, nor in liver and kidney of either species, providing further evidence of a correlation between the occurrence of 30,000 MW Cd-BP protein in the tissue and susceptibility to Cd-injury. The inability of parenterally administered HgCl2 to induce testicular injury compared to the same dose of CdCl2(0.011 mmol/kg) is apparently related to the poor uptake of Hg in the testes (one-eighteenth that of Cd) rather than to an inability of Hg to bind to the 30,000 MW Cd-BP. Our studies indicate that binding of Cd to this unique 30,000 MW testicular component, as yet unidentified, is a possible basis for the unique sensitivity of the testis to Cd injury.     

Synthesis of novel 3'-deoxy-3'-C-hydroxymethyl nucleosides with conformationally rigid sugar moiety as potential antiviral agents

Based on the fact that the ring expanded 3'-C-hydroxymethyl analogue of oxetanocin A exhibited potent antiviral activity, two types of conformationally rigid 3'-C-hydroxymethyl derivatives in which 2'-hydroxyl group is linked to the 4'-position or to the 6'-position were synthesized starting from 1,2;5,6-di-O-isopropylidene-D-glucose, respectively.     

Design and synthesis of thiourea derivatives containing a benzo[5,6]cyclohepta[1,2-b]pyridine moiety as potential antitumor and anti-inflammatory agents

Thiourea derivatives (6a-e) were developed and screened for antitumor and anti-inflammatory activity. Most of the compounds exhibited growth inhibitory effects comparable to 5-fluorouracil in vitro against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. They also showed stronger anti-inflammatory activity than ibuprofen in vivo in the xylene-induced ear swelling assay in mice.