- New heparanase-inhibiting triazolo-thiadiazoles attenuate primary tumor growth and metastasis
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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.
- Barash, Uri,Rangappa, Shobith,Mohan, Chakrabhavi Dhananjaya,Vishwanath, Divakar,Boyango, Ilanit,Basappa, Basappa,Vlodavsky, Israel,Rangappa, Kanchugarakoppal S.
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- Efficient formation of C–S bond using heterocyclic thiones and arynes
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Phenylthio heterocyclic compounds are widely used because of their diverse biological activities and medicinal prospects. Here, a facile method was reported. An arylation of 1,3,4-oxa(thia)diazol-2-thiones reacting with arynes to build C(aryl)-S bonds in the presence of CsF had good yields and excellent selectivity. The reaction was completed in short time without using expensive reagents and catalysts. Present reaction system is an efficient procedure to process phenylthio heterocyclic compounds and reveals a sustainable method and better application prospects in future organic synthesis.
- An, Yu,Xu, Gang,Cai, Menglu,Wang, Shihui,Wang, Xiao zhong,Chen, Yingqi,Dai, Liyan
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- Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin–1,2,4-triazole scaffolds
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Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine–1,2,4-triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods (1H and 13C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram-positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram-negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant-to-moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure–activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad-spectrum antibacterial agents.
- Pathak, Prateek,Novak, Jurica,Shukla, Parjanya K.,Grishina, Maria,Potemkin, Vladimir,Verma, Amita
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- 1,2,4-Triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds: A potent ameliorant of carrageenan-induced inflammation by lessening proinflammatory mediators
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Inflammation acts as an alarming signal for the progression of various biological complications. Various reports in the literature have revealed that heterocycle-containing synthetic compounds have a restorative capability against acute and chronic inflammatory stages. In the current study, we synthesized a series of 1,2,4-triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds and evaluated their impacts against carrageenan-induced paw edema and proinflammatory markers in Wistar rats. Further, 3D QSAR study (three-dimensional quantitative structure–activity relationships), ADMET (absorption, distribution, metabolism, and excretion) profiling, and docking studies were performed to determine the possible mechanism of the action of the derivatives. The study shows that the most active derivatives, 13f and 13g, have optimal logP, a higher anti-inflammatory activity score, and poor metabolism at various sites of cytochrome P450. The docking studies recommended that the synthesized compounds have a similar affinity as the ligands A307, 63X, and S58 to interact with tumor necrosis factor-α, COX-1, and COX-2. So, these molecules will definitely hold a promise for the future drug development initiative.
- Pathak, Prateek,Shukla, Parjanya K.,Naumovich, Vladislav,Grishina, Maria,Verma, Amita,Potemkin, Vladimir
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- Synthesis and antimicrobial activity of piperine analogues containing 1,2,4-triazole ring
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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.
- Kumar, Kottakki Naveen,Amperayani, Karteek Rao,Ummdi, V. Ravi Sankar,Parimi, Uma Devi
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p. 1077 - 1080
(2019/04/05)
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- Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione as antimycobacterial agents
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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.
- Sonawane, Amol D.,Rode, Navnath D.,Nawale, Laxman,Joshi, Rohini R.,Joshi, Ramesh A.,Likhite, Anjali P.,Sarkar, Dhiman
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p. 200 - 209
(2017/07/13)
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- Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis
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Herein, we report the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011-0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.
- Karabanovich, Galina,Zemanová, Júlia,Smutny, Tomá?,Székely, Rita,?arkan, Michal,Centárová, Ivana,Vocat, Anthony,Pávková, Ivona,?onka, Patrik,Něme?ek, Jan,Stola?íková, Ji?ina,Vejsová, Marcela,Vávrová, Kate?ina,Klime?ová, Věra,Hrabálek, Alexandr,Pávek, Petr,Cole, Stewart T.,Miku?ová, Katarína,Roh, Jaroslav
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p. 2362 - 2380
(2016/04/09)
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- Synthesis, Antimicrobial, and Antioxidant Activities of Some Fused Heterocyclic [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazole Derivatives
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In the present work, we synthesized a series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (6a, 6b, 6c, 6d, 6e, 6f and 7a, 7b, 7c, 7d, 7e, 7f) by using simple starting materials, namely, β-amino acids and different aromatic acid hydrazides. The
- Seelolla, Gangadhara,Ponneri, Venkateswarlu
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p. 929 - 936
(2016/05/19)
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- Polyethylene glycol mediated, one-pot, three-component synthetic protocol for novel 3-[3-substituted-5-mercapto-1,2,4-triazol-4-yl]-spiro-(indan-1′,2-thiazolidin)-4-ones as new class of potential antimicrobial and antitubercular agents
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A series of 3-[3-substituted-5-mercapto-1,2,4-triazol-4-yl]-spiro-(indan-1′,2-thiazolidin)-4-ones 2 were designed for the purpose of searching for novel antimicrobial agents and have been synthesized conveniently in a single step with a three-component protocol in polyethylene (400) as green reaction media. Thus, the condensation reaction between indane-1-one; 4-amino-5-mercapto-1,2,4-triazoles and mercaptoacetic acid in polyethylene glycol (400) gave quantitatively and analytically pure titled compounds 2. The structure of synthesized compound 2 is based on spectral (IR, 1H-NMR, and 13C-NMR) as well elemental analyses. These compounds have been screened for their antibacterial, antifungal, and antitubercular activities. Some of them have showed significant inhibition on fungal and bacterial growth and antitubercular activity against Mycobacterium tuberculosis. The compounds 2a, 2d, and 2e display antifungal activity against Candida albicans [minimum inhibitory concentration (MIC) 3.13, 6.25 μg/mL] and antibacterial activity against Streptococcus pneumoniae (MIC 3.13 μg/mL) of the order of standard drugs tested under similar conditions, and compound 2a showed better antitubercular activity than other compounds against M. tuberculosis (H37Rv strain, MIC 12.5 μg/mL).
- Pandey, Sarvesh Kumar,Ahamd, Akeel,Pandey,Nizamuddin, Khan
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p. 1233 - 1239
(2015/04/27)
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- Synthesis and evaluation of novel azoles as potent antifungal agents
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Using a rational approach to the design of antifungal agents, a series of azole agents with 1,3,4-oxadiazole side chains were designed and synthesized. The results of preliminary in vitro antifungal tests with eight human pathogenic compounds showed that all of the title compounds exhibited excellent activities against all of the tested fungi except Aspergillus fumigatus. Compounds 11e and 11f were found to be the most effective, with a minimum inhibitory concentration of 0.0039 μg/mL, followed by voriconazole, which has a MIC of 0.0625 μg/mL. The 1,3,4-oxadiazole side chain is not the major contributor but plays a role in eliciting the observed antifungal activity.
- Li, Liangjing,Ding, Hao,Wang, Baogang,Yu, Shichong,Zou, Yan,Chai, Xiaoyun,Wu, Qiuye
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supporting information
p. 192 - 194
(2014/01/17)
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- Synthesis, docking and evaluation of antioxidant and antimicrobial activities of novel 1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-6-yl)selenopheno[2,3- d]pyrimidines
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A series of 1,2,4-(triazolo[3,4-b][1,3,4]thiadiazol-6-yl)selenopheno[2,3-d] pyrimidines (10a-j) were synthesized with various substituted anilines and benzoic acids. Structures of newly synthesized compounds were established by IR, 1H & 13C NMR and LC-MS spectral data. The antioxidant activity of the synthesized compounds was evaluated by DPPH, NO and H 2O2 radical scavenging methods. The newly synthesized compounds were evaluated for their antimicrobial activity against Gram +ve and Gram -ve bacteria and antifungal activity by well diffusion method. Compounds 10d, 10h and 10i showed promising antioxidant, antibacterial as well as antifungal activity and these were found to be the most potent activity molecules when compared with that of standard drugs. Molecules docking studies have been performed on Staphylococcus aureus (SA) of Gram +ve bacteria.
- Kotaiah,Nagaraju,Harikrishna,Venkata Rao,Yamini,Vijjulatha
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p. 195 - 202
(2014/03/21)
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- Synthesis and antihyperlipidemic activity of some novel 4-(substitutedamino)-5-substituted-3-mercapto-(4H)-1,2,4-triazoles
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Hyperlipidemia is considered one of the key factors for cardiovascular diseases. Based on earlier work on a series of 5-alkyl-4-aryl-3-mercapto-(4H)-1, 2,4-triazoles, for further lead modification, a series of 4-(substituted)amino- 5-substituted-3-mercapto-(4H)-1,2,4-triazoles was designed. Target compounds were synthesized by the well known Hoggarth synthesis of substituted 1,2,4-triazoles. Synthesized compounds were screened for lipid lowering activity using the "Poloxamer 407 induced hyperlipidemia in rats" model at a dose of 100 mg/kg p. o. Compounds were found to alter serum lipid levels significantly. Most of the compounds significantly reduced serum cholesterol and triglyceride levels. Some of the compounds were found to reduce triglycerides and elevate high density lipoprotein (HDL) levels more than the standard drug atorvastatin (CAS 134523-03-8). Compounds with chloro substitution on aryl rings were found more active in reducing serum lipid levels than other substitutions. ECV ? Editio Cantor Verlag.
- Chhabria, Mahesh T.,Suhagia, Bhanubhai N.,Brahmkshatriya, Pathik S.,Raval, Priyesha M.
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experimental part
p. 452 - 457
(2012/06/16)
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- Push-pull azo-chromophores containing two fused pentatomlc heterocycles and their nonlinear optical properties
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We have developed procedures for the synthesis of push-pull azo-chromophores containing the s-triazolo[3,4-b]thiadiazole heterocycle compatible with the presence of electron-acceptor groups (nitrophenyl group) as substituents on both the triazole and thia
- Centore, Roberto,Fusco, Sandra,Peluso, Andrea,Capobianco, Amedeo,Stolte, Matthias,Archetti, Graziano,Kuball, Hans-Georg
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experimental part
p. 3535 - 3543
(2009/12/01)
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- Synthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing γ-butenolide moiety and preliminary evaluation of in vitro anticancer activity
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A new series of chiral 1,3,4-thiadiazoles derivatives possessing γ-substituted butenolide moiety were synthesized and evaluated for in vitro anticancer properties. All the compounds showed good anticancer activities against Hela cell lines. Of all the studied compounds, compound 9e exhibited the best inhibitory activity with an IC50 of 0.9 μM. After being treated with 0.1 μg/mL compound 9e for 24 h, the growth inhibition rate of Hela cell lines was 59.2%.
- Wei, Meng-Xue,Feng, Lei,Li, Xue-Qiang,Zhou, Xue-Zhang,Shao, Zhi-Hui
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scheme or table
p. 3340 - 3344
(2009/12/01)
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- Spectral and equilibrium studies on some new derivatives of 4-amino-5-phenyl-3-mercapto-1,2,4-triazole
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4-Amino-5-phenyl-3-mercapto-1,2,4-triazole (APMT), 4-(4′-methoxy) benzylidineamino-5-phenyl-3-mercapto-1,2,4-triazole (PMBPMT), 4-benzylidineamino-5-phenyl-3-mcrcapto-1,2,4-triazole (BPMT), 4-(2′-hydroxy)benzylidineamino-5-phenyl-3-mercapto-1,2,4-triazole (HBPMT) and 4-amino-5-(4′-nitro)phenyl-3-mercapto-1,2,4-triazole (ANPMT) were synthesized and characterized by elemental analyses, IR, 1H NMR, 13C NMR, DEPT and Mass spectral studies. Proton dissociation constants of these compounds in 70% v/v dioxan water medium at 303 K. and 0.1 M (KNO3) ionic strength were measured. The order of the pKa corresponding to mercapto group follows the sequence : PMBPMT > BPMT > HBPMT > APMT > ANPMT.
- Sireesha, Aliya B.,Reddy, Ch. Venkata Ramana,Devi, Ch. Sarala
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scheme or table
p. 926 - 929
(2009/12/07)
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- Synthesis and in-vitro antimicrobial activity of new 1,2,4-triazoles
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We have described the synthesis of new 1,2,4-triazoles and have evaluated their antimicrobial profile. Antitubercular activity was determined in triplicate using the Lowenstein-Jensen medium. A loopful of Mycobacterium tuberculosis suspension was inoculated on the surface of each Lowenstein-Jensen media containing the test compounds (100, 10 or 1 μg mL-1). To evaluate in-vitro antibacterial activity, compounds (50, 5 or 0.5 μg) were evaluated against B. subtilis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus typhi by the disc diffusion method. To evaluate antifungal activity Sabourauds Dextrose agar medium was used. Some of the compounds (5, 0.5 or 0.05 μg mL-1) were screened for activity against Aspergillus niger 88 and Aspergillus niger 90 and others were screened for activity against T. rubrum TR1, T. rubrum R6, T. rubrum R7 and T. mentagrophyte M1, using the cup plate method. Our results show that the triazoles with a pyrazine moiety at position 3 were more active as antitubercular and antifungal agents compared with the triazoles which had a pyrazine moiety at position 4 of the molecule.
- Bhat,Bhat,Shenoy
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p. 267 - 272
(2007/10/03)
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- Study on the intramolecular Mannich reaction of 4-amino-3-aryl-2,3- dihydrogen-5-mercapto-1,2,4-triazoles
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Seventeen novel fused heterocycles have been prepared by the intramolecular Mannich reaction of 4-amino-3-aryl-5-mercapto-1,2,4-triazole with aldehydes in the presence of acid, Yield: 32 ~ 90%. These compounds were screened for their antimicrobial activities.
- Haijian, Shi,Zhongyi, Wang,Haoxin, Shi
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p. 3973 - 3982
(2007/10/03)
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- Synthesis and a UV and IR spectral study of some 2-aryl-Δ2-1,3,4-oxadiazoline-5-thiones
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Twenty four 2-aryl-Δ2-1,3,4-oxadiazoline-5-thione derivatives 2 were synthesized and their uv and ir spectra were studied. Correlation between σ-Hammett constants of aryl substituents and the differences in absorption maxima (Δν = ν1-ν2 in kK) of the electronic spectra of the deprotonated species were also evaluated. A new method for the synthesis of the 2-(amino)aryl derivatives 2v,w,x is also reported.
- Charistos,Vagenas,Tzavellas,Tsoleridis,Rodios
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p. 1593 - 1598
(2007/10/02)
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- A Novel Synthesis of Peptide Based on the Photochemistry of 5-Azido-1,3,4-oxadiazoles
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A novel approach to the synthesis of peptides is described.Various N-protected amino acid hydrazides 17 were converted to the salts 18 by condensation with carbon disulfide in methanolic potassium hydroxide.Thermal cyclization of 18 to the heterocycles 19 was followed by reaction with methyl iodide to yield the sulfides 20.After oxidation of 20 to the corresponding sulfones 21, the title compounds 22 were prepared by treating 21 with sodium azide.Deprotection then yielded the free bases 23.Utilization of 22 and 23 in peptide synthesis, relying on a photochemical degradation of the title heterocycle present in these compounds, is described.The scope and limitations of this new methodology are also discussed.
- Confalone, Pat N.,Woodward, Robert B.
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p. 902 - 906
(2007/10/02)
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- THE ACIDITIES AND THE TAUTOMERIC STRUCTURE OF 5-ARYL-2-MERCAPTO-1,3,4-OXADIAZOLES
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The acidity constants of a series of substituted 5-phenyl-2-mercapto-1,3,4-oxadiazoles were determined by potentiometric and spectrophotometric methods in 80percent (vol.) ethanol-water at 25 deg C.The data obtained by the two methods are in good agreement.The pKa values correlate with the ?*XC6H4 constants of the substituted phenyl group (p = -0.985, r = 0.936), however, a better correlation of the pKa data with the Hammett substituent constants ?X (p = -0.983, r = 0.959) was obtained.These linear correlations exclude the possibility of the presence of the thiol tautomer 1 in eqiulibrium with the thioamide tautomer 2 and indicate that the ionization of the compounds takes place in the form of the thioamide tautomer 2.According to the results of the HMO calculations, the thioamide form 2 is more stable than the thiol tautomer 1.A satisfactory correlation between the observed pKa values and the difference between the ?-electronic energies (ΔE?) of the thioamide tautomer and of the common resonance-stabilized anion was obtained, thus supporting the assigned tautomeric structure 2 for the series under study.
- Shawali, Ahmad S.,Rizk, Mahmoud S.,Abdelhamid, Abdou O.,Abdalla, Magda A.,Parkanyi, Cyril,Wojciechowska, Magdalena E.
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p. 2211 - 2224
(2007/10/02)
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