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Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC50 value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC50 value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.

The invention belongs to the technical field of medicines, and relates to a dammarane sapogenin derivative and a preparation method and application thereof. A series of dammarane sapogenin derivativesare obtained by combining dammarane sapogenins from plants with different groups. Anticancer activity evaluation and anticancer activity mechanism research are carried out on the derivative, and results show that the prepared dammarane sapogenin derivative has a remarkable anticancer effect, has no toxic effect on normal cells and can be used for preparing drugs for treating cancers.

The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of 5l against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.

In this study, we introduced 1, 2, 4-triazole groups into panaxadiol (PD) to obtain 18 panaxadiol triazole derivatives. Five cancer cells and one normal cell were evaluated for cytotoxicity by MTT assay. The results showed that most of the derivatives could inhibit cancer cell proliferation, and the anti-proliferative activity of compound A1 was the most significant. For HepG-2 cells, the IC50 value was 4.21 ± 0.54 μM, which was nearly 15 times higher than the activity of PD. Further studies showed that compound A1 could induce apoptosis in HepG-2 cells, and could enhance the expression of Cl-caspase-3, Cl-caspase-9 and Cl-PARP. Moreover, Western blot analysis showed that after treating HepG-2 cells with compound A1, the expression of p53 protein was increased and the ratio of Bax/Bcl-2 was gradually increased. The cytoplasmic Bax is then translocated to the mitochondria, causing the release of Cyt c protein. Therefore, the results indicate that compound A1 induces apoptosis through the mitochondrial pathway and can be used the potential to develop new anti-proliferative agents.

Thymidine phosphorylase (TP) is over expressed in several solid tumors and its inhibition can offer unique target suitable for drug discovery in cancer. A series of 1,2,4-triazoles 3a–3l has been synthesized in good yields and subsequently inhibitory potential of synthesized triazoles 3a–3l against thymidine phosphorylase enzyme was evaluated. Out of these twelve analogs five analogues 3b, 3c, 3f, 3l and 3l exhibited a good inhibitory potential against thymidine phosphorylase. Inhibitory potential in term of IC50 values were found in the range of 61.98 ± 0.43 to 273.43 ± 0.96 μM and 7-Deazaxanthine was taken as a standard inhibitor with IC50 = 38.68 ± 4.42 μM. Encouraged by these results, more analogues 1,2,4-triazole-3-mercaptocarboxylic acids 4a–4g were synthesized and their inhibitory potential against thymidine phosphorylase was evaluated. In this series, six analogues 4b–4g exhibited a good inhibitory potential in the range of 43.86 ± 1.11–163.43 ± 2.03 μM. Angiogenic response of 1,2,4-triazole acid 4d was estimated using the chick chorionic allantoic membrane (CAM) assay. In the light of these findings, structure activity relationship and molecular docking studies of selected triazoles to determine the key binding interactions was discussed. Docking studies demonstrate that synthesized analogues interacted with active site residues of thymidine phosphorylase enzyme through π-π stacking, thiolate and hydrogen bonding interactions.

In this study, four novel series of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of ?48.22?±?0.36% at a concentration of 3?×?10?5?mol/L (metoprolol: ?9.74?±?0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP-sensitive K+ channel and L-type Ca2+ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria.

Abstract: A series of N′-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohydrazide were synthesized. Condensation of aromatic aldehydes with 2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohydrazide gave corresponding N′ -arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohydrazide. Spectral and elemental analysis was used for structural elucidation of novel 1, 2, 4-triazole schiff bases. The newly synthesized compounds were screened for their antidepressant activity by using tail suspension test in mice. Compound 4l showed significant activity among the series. Graphical Abstract: A series of new N′-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio)acetohydrazide have been synthesized and characterized. The results revealed that compound 4l with bromo substitution exhibited promising antidepressant activity among the series. [InlineMediaObject not available: see fulltext.].

Background: Research on the synthesis of anticonvulsants is still in progress as they produce adverse effects with lesser activity as well as the patients become resistant to drug therapy. 1,2,4-triazole scaffold is a resource for the synthesis of anticonvulsant agents having better pharmacological action. Virtual Screening plays an important role to achieve binding affinity, receptor and library pre-processing, docking, scoring and top scoring hits. Optimization of drug ADME parameters continues to play an important role to achieve proof of concept, and ultimately efficacy, safely in clinical trials to address unmet medical need. Objective: The aim was to design, synthesise and evaluate anticonvulsant activity of a series of 5-substituted-2-(2-(5-aryl-1H-1,2,4-triazole-3-ylthio)acetyl) hydrazine carbothioamide/ carboxamides along with their in silico properties. Methods: Derivatives of 5-substituted-2-(2-(5-phenyl-1H-1,2,4-triazol-3-ylthio)acetyl)hydrazine carboxamides/ carbothioamides were obtained by condensation of Ethyl-2-(5-aryl-1H-1,2,4-triazol-3-ylthio)acetates with thiosemicarbazide or semicarbazide. The synthesized compounds were characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (1H NMR) and mass spectrometry (MS) while their anticonvulsant activity was screened against pentylenetetrazole-induced seizure (PTZ) against diazepam as reference standard. Molecular docking (in silico) studies were performed using 4-aminobutyrateaminotransferase in order to predict possible protein-ligand interactions. Results: Among the target compounds, 3f exhibited lower activity with 50% protection. The compounds 3e and 3h showed good to moderate levels of anticonvulsant activity with 83.3% protection at 100 mg/kg. The compounds 3g and 3i showed most significant anticonvulsant activity with 100% protection at a dose of 30 mg/kg. In silico results also revealed that 3g and 3i have shown maximum binding affinity to GABA AT protein among the tested compounds. Conclusion: The synthesized compounds showed potent anticonvulsant activity. Molecular docking results should give an insight into how further modification of lead compound can be carried out for higher inhibitory activity.

The invention discloses a 6-methyl-thiazole [3,2-b] [1,2,4]-triazole-5-formamide derivative as shown in formula I or pharmaceutically acceptable hydrate and salt thereof, including stereisomer or tautomer thereof. In the formula I, R1 is hydrogen, methyl, halogen, hydroxy, methoxyl, acetyl, propionyl, nitryl or alkoxy; R2 and R3 are independently selected from C1-C6 alkyl; or R2, R3 and nitrogen atoms connected with R2 and R3 form pyrrolyl, piperidyl, morpholinyl, N-methyl piperazine and N-(4-bromophenyl) piperazine. The 6-methyl-thiazole [3,2-b] [1,2,4]-triazole-5-formamide derivative disclosed by the invention is used as a vascular endothelial growth factor protein tyrosine kinase inhibitor for treating and preventing various cancers.

The invention discloses a 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative with a general formula I, or a pharmaceutically acceptable aquo-complex and salts of the derivative; the derivative comprises a stereisomer or a tautomer, wherein R1 and R2 in the formula I are respectively independent hydrogen, methyl, halogen, hydroxyl, methoxyl, acetyl, propiono, nitro or alkoxy. The 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative has an obvious inhibiting effect on acetylcholin esterase, and is used for improving the memory of a patient suffering from dementia and Alzheimer's disease. The invention also relates to a preparation method of the compound and an application in preparation of a drug for treating Senile Dementia.

Resistance among dormant mycobacteria leading to multidrug-resistant and extremely drug-resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione derivatives (4a–5c) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC50) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram-negative and Gram-positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100?μg/ml against THP-1, A549, and PANC-1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.

The invention discloses a thiazole [3,2-b] [1,2,4]-triazole-6-acetamide derivative as shown in formula I or a pharmaceutically acceptable hydrate and salt thereof. The derivative comprises a stereisomer or tautomer thereof; R1 in the formula I is hydrogen, methyl, halogen, hydroxy, methoxy group, acetyl, propionyl, nitro or alkoxy; R2 and R3 are independently selected from C1-C6 alkyl or R2 and R3 and nitrogen atoms connected with the R2 and R3 are formed into pyrryl, piperidyl, morpholinyl, N-methyl piperazine and N-phenylpiperazine. The thiazole [3,2-b] [1,2,4]-triazole-6-acetamide derivative disclosed by the invention has an obvious restraining function to acetylcholin esterase and is used for enhancing the memory of the patients suffering from dementia and Alzheimer's disease. The invention also relates to a preparation method of the compound and application of the compound for preparing the drug for treating the senile dementia.

A series of diethyl (3-((5-aryl-1H-1,2,4-triazol-3-yl)thio)propyl)phos-phonates (7a-t) has been synthesized in excellent yields by coupling diethyl (3-bromopropyl)phosphonate and 5-aryl-1H- 1,2,4-triazol-3-thiones employing an efficient, green and nonconventional heterogeneous SO3Hcarbon catalyst derived from glycerol. In addition, a facile and green approach for the esterification of carboxylic acids by utilizing glycerol-based solid acid catalyst has been reported. Structures of the synthesized compounds were characterized by IR, NMR and HRMS studies. These triazole derivatives were screened for their in vitro cytotoxicity using the standard MTT (3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyltetra-zolium bromide) assay against a panel of five different human cancer cell lines (HeLa: Cervix, A549: Lung, A375: Skin, MDA-MB-231: Breast and T98G: Brain). The antimicrobial activities of the synthesized compounds were investigated against four bacterial strains: Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and three fungal strains: Aspergillus Niger, Aspergillus terreus, Aspergillus fumigatus. Preliminary results indicate that the compound 7f displayed maximum anticancer activity and the compounds 7d, 7e, 7f, 7m and 7q exhibited moderate antibacterial activity. The compounds 7g, 7h, 7o and 7p showed good antifungal activity with high inhibition zone diameter compared to the standard drug.

Disclosed herein are novel five membered heterocyclic compounds of Formula (I) wherein, X is S or SO2; n is 0, 1; m is1 or 2; Y is N, O or S; R2 independently represents H or alkyl or halo selected from -CI, -F; or -CF3, or -OH or-NH2 or - NO2; and R1 independently represents H or C1 to C5 straight or branched chain alkyl, alkenyl, alkynyl or a group -(CH2)5Br or pyrrolidine or - NHR' wherein R' is H or isopropyl or (II) or (III) which selectively act against dormant pathogenic tuberculi bacilli and exhibit antiproliferative activities and for treatment of a disease or disorder associated with GroEL1/GroEL2 activity. The invention relates to a process for preparation of novel five membered heterocyclic compounds of Formula I and to pharmaceutical compositions thereof.

In this study, the synthesis, anti-inflammatory and analgesic activities of eight new 5-thioalkyl-1,3-diaryl-1,2,4-triazole derivatives were reported. For the anti-inflammatory study, the carrageenan-induced rat paw edema model was used. The test compounds in 50 mg/kg and 100 mg/kg were injected as IP and paw edema was determined. The results showed that some of the compounds have good activity compared to the references drug, indomethacin. For analgesic activity, the test compounds were studied using the in Tail-flick test model in 50 and 100 mg/kg as IP injections. Their analgesic activities were determined after 30 min via latency time assay. Statistical analysis showed that all test compounds have antinociceptive activity in the range of 24% -47% as compared to the control with a dose of 50 mg/kg. However, all tested compounds have analgesic activity lower than the standard drug, morphine.

An efficient, green, and chemoselective S-alkylation of 5-aryl-1H-1,2,4-triazole-3-thiones with diethyl (3-bromopropyl)phosphonate in water, catalyzed by nano-Fe2O3 under ligand-and base-free conditions, is reported. Clean reaction, less expensive catalyst, excellent yields, and easy workup are the advantages of the present method. The catalyst can be easily collected by a magnet and recycled without significant loss in catalytic activity. The newly synthesized compounds were screened for their antioxidant property by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay. The majority of the compounds exhibited good antioxidant activity.

A series of 3-[3-[4-(substituted)-1-cyclicamine] propyl]thio-5- substituted[1,2,4]triazoles (8a-m) and 2-[3-[4-(substituted)-1-cyclicamine] propyl]-5-(substituted)-2,4-dihydro-3H[1,2,4]triazole-3-thiones (9a-h) were synthesized with good yields starting from corresponding carboxylic acids using two different methods. The cytotoxicity studies of these derivatives were studied against five different human cancer cell lines. Six compounds had shown good anticancer activity. The triazole derivatives, 9d, 8j, and 8i were most potent particularly against U937 and HL-60 cells. The cytotoxic potency of the compounds varied between the cell lines suggesting that a structural property of these compounds as possible determinant of their biological activity. Springer Science+Business Media 2013.

A series of 5-Aryl-1H-1,2,4-triazole-3-thiol (3) were synthesized. Alkylation of thiol group with N,Ndimethyl/ diethyl/dicyclo hexyl-(2-chloro ethyl) amine gave compounds N,N-disubstituted-2-(5-Aryl-1H-1,2,4-triazol-3- ylthio)ethanamine (4). These compounds were characterized on the basis of IR, 1H NMR, Mass spectral data, and elemental analysis. The newly synthesized compounds were screened for their antidepressant activity by using tail suspension test in mice. Springer Science+Business Media, LLC 2011.

A series of 3-[3-[4-(Substituted)-1-cyclicamine]propyl]thio-5- substituted[1,2,4]triazoles (8a-j) were synthesized with good yields starting from corresponding carboxylic acids. The cytotoxicity studies of these derivatives were studied against five different human cancer cell lines. Three compounds had shown good anticancer activity. The triazole derivatives, 8i and 8j were most potent particularly against U937 and HL-60 cells. The cytotoxic potency of the compounds varied between the cell lines suggesting that a structural property of these compounds as possible determinants of their biological activity.

In order to develop potent analgesic/antiinflammatory compounds with reduced ulcerogenic risk, a series of thiazolotriazolyl-carboxylic and acetic acid esters were synthesized and characterized by spectral and elementary analysis. All synthesized compounds were screened for in vivo anti-inflammatory activities in mice by carregeenan-induced paw edema model. The compounds showing 20% reduction in paw edema were also evaluated for their analgesic activities by acetic acid-induced writhing test and the gastric ulceration risk by determining the lipid peroxidation level in stomachs. Among the compounds tested, compounds 1, 4, 6, 7, 8, 1a, 2a, 3a, 4a, 7a, 2b, and 8b showed moderate-to-good anti-inflammatory activity at various doses in any of the measurement intervals. Compounds 7a, 2b, and 8b were the most actives of the series in analgesic activity test. Moreover, compounds 1, 4, and 8 were found to be safe in stomach in respect of free radical production. Springer Science+Business Media, LLC 2010.

A mild, convenient, and efficient one-pot synthesis of mercapto-1,2,4- triazoles is described. Various hydrazides efficiently reacted with trimethylsilyl isothiocyanate (TMSNCS) under basic condition to give mercapto-1,2,4-triazoles in high yields.

Novel thiazolidinedione derivatives were synthesized by incorporating pharmacologically significant heterocycles viz, substituted thiazole, triazole, and oxadiazole moieties linked to the central phenyl ring via heteroatomlinkage with one/two carbon spacer as the structural analogs of Pioglitazone by employing multistep synthetic protocols. Structures of all the newly synthesized intermediates and target molecules were established by analytical and spectral data. These newly synthesized compounds were screened for their invivo hypoglycemic and hypolipidemic activities in male wistar rats. Some of the synthesized compounds demonstrated good activity.

Several new 5-aryl-3-(β-D-glucopyranosylthio)-1,2,4-triazoles have been synthesized. The structures of these new compounds were confirmed by 1H NMR, 13C NMR and elemental analyses.The antibacterial activities of the compounds were also evaluated.

A series of 3-aryl-4H-5-(61/81-substituted-31-formyl-21-quinolinyl) thia-1,2,4-triazoles were prepared by the reaction of 2-chloro-3-formyl-6/8- substituted quinoline with 3-substituted 4H-5-mercapto-1,2,4-triazole. These thia-triazoles 5 on reaction with substituted acetophenone gave a novel series of 2-substituted-s-triazolo[5,1-b]-6/8-substituted quinolino-9-arylacetyl[1,3] thiazines 8 rather than the expected 1-aryl-3-[21-(5-substituted-4H-1,2,4- triazole-5-thia)-61/81-substituted quinoline-31-yl]-2-propen-1-ones 7. The new compounds were screened for their antibacterial activity against Gram-positive and Gram-negative bacteria and antifungal activity against Candida albicans. Most of the tested compounds showed significant antibacterial activity much higher than that of the standard drug Nitrofurazone. The structures of the new compounds were established based on analytical and spectral data. In a typical example, the structure of thiazine 8e was further confirmed by single crystal x-ray data. Copyright Taylor & Francis Group, LLC.

N-(Substituted benzoyl) thiosemicarbazides 11a-e were treated with sodium hydroxide solution to give 3-aryl-5-mercapto-4H-1,2,4-triazole 111a-e which were subjected to Mannich Reaction in presence of 2-OC2H5, 4-NO2 and 2-OCH3 substituted anilines to give 3-aryl 7H, 6-(aryl) 5H-1,2,4-triazolo [3,4-b]-1,3,5-thiadiazines IVa-h. The compounds, IVa-h were compared with oxytetracycline and ampiclox (standard antibiotics) for their antibacterial activity.

Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones (4-10) were obtained in a one step synthesis by heating 3-aryl-5-mercapto-1,2,4-triazoles (3a-d) with chloroacetic acid and appropriate aromatic aldehyde in acetic acid and acetic anhydride in the presence of anhydrous NaOAc. Michael type addition of cyclic secondary amines (N-methylpiperazine, piperidine) to 4-10 gave 2-phenyl-6- (α-aminoarylmethyl)thiazolo[3,2-b]-1,2,4-triazole-5-ols (4a-10b). The structures of the compounds were confirmed by spectral and elementary analysis. The compounds synthesized in previous and present studies were investigated for their anti-inflammatory activities.

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A series of 5-aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones was prepared and evaluated for potential antidepressant activity.Members of this series were generally prepared by the alkaline ring closures of the corresponding 1-aroylthiosemicarbazides.Several

A new general synthesis of 4,5-disubstituted 2,4-dihydro-1,2,3-triazole-3-thiones is proposed.These heterocycles are obtained by the action of primary amines, aralhydrazines or aroylhydrazines on the thiosemicarbazones of esters.These last compounds are prepared by action of chlorhydrates of iminoesters on thiosemicarbazide in dimethylformamide.These thiosemicarbazones react also with strong acids, acid anhydrides and chlorides; by thermolysis and they give 2-amino-1,3,4-thiadiazole derivatives.Also, two derivatives of 1,2,4-triazolo-1,3,4-thiadiazole have been prepared.

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During the synthesis of thiazolotriazolylacetic acids, the condensation of ethyl 4-chloro-3-oxobutyrate with triazolinethiones was studied.The use of an alkaline reagent (triethylamine) leads only to S-alkylation and not to the expected cyclized product.T

Cyclization of 1-aroylthiosemicarbazides (I) under alkaline conditions gives 3-mercapto-5-aryl-s-triazoles (II), while their condensation with 2-chlorocyclohexanone (IIIa) furnishes 2-aroylhydrazino-4,5,6,7-tetrahydrobenzothiazoles (IV).The reaction of II with IIIa affords 2-aryl-5,6,7,8-tetrahydro-s-triazolobenzothiazoles (Va).Structure of Va has been established by comparison with isomeric 3-aryl-5,6,7,8-tetrahydro-s-triazolobenzothiazoles (VI), obtained by cyclization of IV.The reaction of 2-bromo-6-carbethoxycyclohexanone (IIIb) with II does not produce the expected 5-carbethoxy-2-aryl-5,6,7,8-tetrahydro-s-triazolo benzothiazoles (Vb), but gives Va.Hydrolysis and decarboxylation of Vb during the reaction to form Va are discussed.