68468-95-1

Usage

InChI:InChI=1/C8H7ClN4S/c9-6-3-1-5(2-4-6)7-11-12-8(14)13(7)10/h1-4H,10H2,(H,12,14)

Upstream product

• 38539-88-7 potassium p-chlorobenzoylhydrazinodithioformate 
• 74-11-3 para-chlorobenzoic acid 
• 1126-46-1 Methyl 4-chlorobenzoate 
• 2231-57-4 Thiocarbohydrazide 
• 75-15-0 carbon disulfide 
• 23766-28-1 5-(4-chlorophenyl)-2,3-dihydro-1,3,4-oxadiazole-2-thione 
• 536-40-3 4-chlorobenzoic acid hydrazide 
• 7335-27-5 ethyl 4-chlorobenzoate 
• 10364-95-1 1-(4-chloro-benzoyl)-1H-imidazole 
• 96951-77-8 N'-(4-Chloro-benzoyl)-hydrazinecarbodithioic acid 
• 23766-28-1 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol 

Downstream Products

• 120450-03-5 2-(4-Chloro-phenyl)-9-thia-1,3,3a,8-tetraaza-cyclopenta[b]naphthalen-4-one 
• 116859-52-0 2-(((5-p-chlorophenyl-4-amino-1,2,4-triazol-3-yl)thio)methyl)-1H-benzimidazole 
• 139268-00-1 4-<5-(4-p-Chlorophenyl)-2-furfurylidene>amino-3-mercapto-5-p-chlorophenyl-1,2,4-triazole 
• 139268-18-1 6-<5-(4-Chlorophenyl)-2-furyl>-3-p-chlorophenyl-1,2,4-triazolo<3,4-b>-1,3,4-thiadiazole 
• 108222-56-6 3-(4-chlorophenyl)-6-(2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 
• 139268-06-7 6-<5-(4-Nitrophenyl)-2-furyl>-3-p-chlorophenyl-1,2,4-triazolo<3,4-b>-1,3,4-thiadiazole 
• 111828-04-7 (4-amino-5-p-chlorophenyl-4H-1,2,4-triazol-3-ylsulphanyl)-methylenenitrile 
• 111828-10-5 [4-Amino-5-(4-chloro-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetic acid methyl ester 
• 132818-41-8 3-(4-Chloro-phenyl)-7-phenyl-6-p-tolyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 
• 132818-42-9 3,6-Bis-(4-chloro-phenyl)-7-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 
• 139268-12-5 6-<5-(4-Bromophenyl)-2-furyl>-3-p-chlorophenyl-1,2,4-triazolo<3,4-b>-1,3,4-thiadiazole 
• 111827-97-5 C₁₇H₁₄Cl₂N₈S₂ 
• 150536-08-6 [3-(4-Chloro-phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl]-acetic acid ethyl ester 
• 133842-64-5 3-(4-Chloro-phenyl)-8-methyl-6,8a-dihydro-pyrazolo[3,4-e][1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 

Relevant academic research and scientific papers

New heparanase-inhibiting triazolo-thiadiazoles attenuate primary tumor growth and metastasis

Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo–thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.

4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors

Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the μM to sub-μM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several β-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.

Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study

Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.

Synthesis and computational studies of highly selective inhibitors of human recombinant tissue non-specific alkaline phosphatase (h-TNAP): A therapeutic target against vascular calcification

In this study, we have discovered small druglike molecules as selective inhibitors of human tissue-nonspecific alkaline phosphatase (h-TNAP), an enzyme critical for the regulation of extracellular matrix calcification. The upregulation of h-TNAP is associated with various pathologies particularly the vascular calcification (VC). Selective inhibition of h-TNAP over h-NPP1 may serve as a useful therapeutic strategy against vascular calcification. A series of novel triazolyl pyrazole derivatives (10a-y) in which thiol bearing triazole moiety as the zinc binding functional group was introduced to a pyrazole based pharmacophore was synthesized and evaluated as potent and selective inhibitors of h-TNAP over h-NPP1. The biological screening against h-TNAP, h-IAP, h-NPP1 and h-NPP3 showed that many of the synthesized compounds are selective inhibitors of TNAP. Particularly, the compounds 10a-h, 10j, 10m-q, 10u, 10w and 10x displayed high potency and complete selectivity towards h-TNAP over h-NPP1. Compound 10q emerged as a highly potent inhibitor (IC50 = 0.16 μM or 160 nM) against h-TNAP with 127-fold increased inhibition compared to levamisole. On the other hand, compound 10e was found to be most selective inhibitor against the tested APs and NPPs (IC50 = 1.59 ± 0.36 μM). Binding sites architecture analysis, molecular-docking and molecular dynamics simulations (MDS), revealed the basis for h-TNAP and h-IAP ligand selectivity as well as selectivity towards h-TNAP over h-NPP1. These newly discovered inhibitors are believed to represent valuable lead structures to further streamline the generation of candidate compounds to target VC.

Investigation of potent inhibitors of cholinesterase based on thiourea and pyrazoline derivatives: Synthesis, inhibition assay and molecular modeling studies

Owing to the desperate need of new drugs development to treat Alzheimer's ailment the synthesis of 1-aroyl-3-(5-(4-chlorophenyl)-1,2,4-triazole-3-thioneaminylthioureas (2–6) starting from (4-amino-5-(4-chlorophenyl)-4H-1,2,4-triazole-3-thiol) (1) and synt

Synthesis and antimicrobial activity of piperine analogues containing 1,2,4-triazole ring

A series 1,2,4-triazole piperine analogues (TP1-TP6) were designed and synthesized. The structures were confirmed using 1H NMR and 13C NMR. Antibacterial study was done using Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram-negative microorganisms (E. coli and Pseudomonas aeruginosa) by disc diffusion method. Compound containing chloro substitution (TP6) showed the highest effect, while compound TP1, TP3, TP4, TP5 showed the moderate activity.

Synthesis and antitumor evaluation of novel fused heterocyclic 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives

In this study, twenty three 3,6-disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives were synthesized and their antiproliferative activities in vitro were studied against SMMC-7721, HeLa, A549, and L929 by the CCK-8 assay. The bioassay results demonstrated that all tested compounds 8(a–w) exhibited antiproliferation with different degrees, and some compounds showed better effects than reference drug 5-fluorouracil. Among these screened compounds, compounds 8a, 8d, and 8l displayed significant antitumor activities in inhibiting SMMC-7721cell proliferation with IC50 values of 1.64, 1.74, and 1.61 μM, respectively. Compounds 8d and 8l were manifested highly effective biological activity versus HeLa cells with IC50 values of 2.23 and 2.84 μM, respectively. Compound 8l was found to have the highest antitumor potency against A549 cells with IC50 value of 2.67 μM. Furthermore, all compounds exhibited weaker cytotoxic effects than 5-fluorouracil on normal cell lines L929.

Design, Synthesis and Evaluation of Antitubercular Activity of Novel 1,2,4-Triazoles Against MDR Strain of Mycobacterium tuberculosis

Emergence of various forms of resistant strains of Mycobacterium tuberculosis led to the exploration of drugs with novel mechanism of action. Recently econazole, an azole based antitubercular agent, attracted major attention for targeting mycobacterial cytochrome P450. In the present study, we designed novel 1,2,4-triazole derivatives based on econazole moiety and evaluated them for in vitro antitubercular activity against M. tuberculosis H37Rv and multi-drug resistant (MDR) strains of Mycobacterium.

Synthesis of some novel imidazoles catalyzed by Co3O4 nanoparticles and evaluation of their antibacterial activities

Aim and Objective: The multi-component condensation of benzil, primary amines, ammonium acetate and various aldehydes was efficiently catalyzed using cobalt oxide nanoparticles under ultrasonic irradiation. This approach describes an effective and facile method for the synthesis of some novel 1,2,4,5-tetrasubstituted imidazole derivatives with several advantages such as high yields and short reaction times and reusability of the catalyst. Moreover, the prepared heterocyclic compounds showed high antibacterial activity against some pathogenic strains. Materials and Method: The facile and efficient approaches for the preparation of Co3O4 nanoparticles were carried out by one step method. The synthesized heterogeneous nanocatalyst was characterized by spectroscopic analysis including EDX, FE-SEM, VSM, XRD and FT-IR analysis. The as-synthesized cobalt oxide nanoparticles showed paramagnetic behaviour in magnetic field. In addition, the catalytic influence of the nanocatalyst was examined in the one-pot reaction of primary amines, benzil, ammonium acetate and diverse aromatic aldehydes under ultrasonic irradiation. All of the 1,2,4,5-tetrasubstituted imidazoles were investigated and checked with m.p., 1H NMR, 13C NMR and FT-IR spectroscopy techniques. The antibacterial properties of the heterocycles were evaluated in vitro by the disk diffusion against pathogenic strains such as Escherichia coli (EC), Bacillus subtillis (BS), Staphylococcus aureus (SA), Salmonellatyphi (ST) and Shigella dysentrae (SD) species. Results: In this research cobalt oxide nanostructure was used as a robust and green catalyst in the some novel imidazoles. The average particle size measured from the FE-SEM image is found to be 20-30 nm which confirmed to the obtained results from XRD pattern. Various electron-donating and electron-withdrawing aryl aldehydes were efficiently reacted in the presence of Co3O4 nanoparticles. The role of the catalyst as a Lewis acid is promoting the reactions with the increase in the electrophilicity of the carbonyl and double band groups. To investigate the reusability of the catalyst, the model study was repeated using recovered cobalt oxide nanoparticles. The results showed that the nanocatalyst could be reused for five times with a minimal loss of its activity. Conclusion: We have developed an efficient and environmentally friendly method for the synthesis of some tetrasubstituted imidazoles via three-component reaction of benzil, primary amines, ammonium acetate and various aldehydes using Co3O4 NPs. The present approach suggests different benefits such as: excellent yields, short reaction times, simple workup procedure and recyclability of the magnetic nanocatalyst. The prepared 1,2,4,5-tetrasubstituted imidazoles revealed high antibacterial activities and can be useful in many biomedical applications.

Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains

Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure–activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv?=?0.25?μg/mL; MIC-MDRTB?=?2.0?μg/mL; MIC-RDRTB?=?0.25?μg/mL; Mt SD-IC50?=?86.39?μg/mL; and 6g-3, MIC-H37Rv?=?1.0?μg/mL; MIC-MDRTB?=?4.0?μg/mL; MIC-RDRTB?=?2.0?μg/mL; Mt SD-IC50?=?73.57?μg/mL). Compounds 6c-3 and 6g-3 possessed a para-nitro phenyl at the 6 position showed low Vero and HepG2 cells toxicity, turning out to be two excellent lead candidates for preclinical trials. In addition, in vitro Mt SD inhibitory assay indicates that Mt SD is at least one of the targets for their antitubercular activity. Thus, they may turn out to be promising multidrug-resistance-reversing agents.