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In an effort to develop new inhibitors of metallo-β-lactamases (MβLs), twenty-eight azolylthioacetamides were synthesized and assayed against MβLs. The obtained benzimidazolyl and benzioxazolyl substituted 1–19 specifically inhibited the enzyme ImiS, and 10 was found to be the most potent inhibitor of ImiS with an IC50 value of 15 nM. The nitrobenzimidazolyl substituted 20–28 specifically inhibited NDM-1, with 27 being the most potent inhibitor with an IC50 value of 170 nM. Further studies with 10, 11, and 27 revealed a mixed inhibition mode with competitive and uncompetitive inhibition constants in a similar range as the IC50 values. These inhibitors resulted in a 2–4-fold decrease in imipenem MIC values using E. coli cells producing ImiS or NDM-1. While the source of uncompetitive (possibly allosteric) inhibition remains unclear, docking studies indicate that 10 and 11 may interact orthosterically with Zn2 in the active site of CphA, while 27 could bridge the two Zn(II) ions in the active site of NDM-1 via its nitro group.

Triazoles and their heterocyclic analogues are nitrogen-rich versatile pharmacophores easily synthesized and converted to a range of biologically relevant heterocycles. In this context, the present research reports the synthesis, characterization, in vitr

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.

Some novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were synthesized from aryl acetic acids. All the synthesized derivatives were selected for the screening of antibacterial potential against Gram-positive bacteria [Staphylococcus aureus (MTCC 3160) and Micrococcus luteus (MTCC 1538)] and Gram-negative bacteria [Escherichia coli (MTCC 1652) and Pseudomonas aeruginosa (MTCC 424)] and antifungal potential against Aspergillus niger (MTCC 8652) and Candida albicans (MTCC 227), and free radical scavenging activity through 2,2-diphenyl-2-picrylhydrazyl hydrate method. The compounds TH-4, TH-13, and TH-19 were found to be more potent antimicrobial agents compared to standard drugs. The compounds TH-3, TH-9, and TH-18 also showed significant antimicrobial activity. The compound TH-13 showed antioxidant activity with IC50 value better than the standard compound. The structures of all the synthesized compounds were confirmed by Fourier transform infrared, 1H-NMR, liquid chromatography–mass spectrometry, and CHN analyzer.

A series of 1,2,4-triazole-3-thione derivatives (6a–6t) were synthesized and evaluated against influenza viruses (H1N1) neuraminidase (NA) in vitro. Eighteen compounds exhibited inhibitory potency with IC50 values ranging from 14.68?±?0.49 to 39.85?±?4.23?μg/mL. Among them, compounds 6e and 6h showed significant inhibitory activity with IC50 values of 14.97?±?0.70 and 14.68?±?0.49?μg/mL, respectively. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction between active compounds and NA.

Compounds and salts thereof which are acyl-sulfonamides or certain carboxylic acids and which inhibit microbial growth or attenuate the virulence of pathogenic microorganisms and which inhibit UDP-galactopyranose mutase (UGM). Compounds of the invention include 2-aminothiazoles and triazolothiadiazines, particularly 3,6,7-substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, and 2-amino and salts thereof. Methods for inhibiting growth or attenuating virulence of microbial pathogens including mycobacterium, for example, M. tuberculosis and M. smegmatis and Klebsiella, for example, Klebsiella pneumoniae. Methods for inhibiting eukaryotic human and animal pathogens, and fungi and nematodes in particular. Methods for treatment of infections by prokaryotic and eukaryotic pathogens employing compounds of the invention.

Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole–thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.

Isatin (2,3-dioxindole) and its derivatives show a wide range of biological activities. In the present study, a series of Schiff and Mannich bases of isatin derivatives were prepared using 4-amino-5-benzyl-2,4-dihydro-3H- 1,2,4-triazole-3-thione. The stru

In this study, a series of 3,6-disubstituted-1,2, 4-triazolo-[3,4-b]-1,3,4- thiadiazoles (5a-t) were synthesized by condensing 4-amino-3-mercapto-(4H)-1,2, 4-triazoles (4a-c) with different aromatic or aroyl acids through one-pot reaction. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation actions. Some of the newly synthesized compounds showed very good anti-inflammatory activity with low GI toxicity and reduced lipid peroxidation. These compounds also showed interesting profile of analgesic activity in acetic acid-induced writhing test. The findings of the study indicate that the synthesized compounds have superior GI safety profile along with reduction in lipid peroxidation as compared to that of the standard. Springer Science+Business Media, LLC 2010.

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.

Employing basic principles of solution phase combinatorial chemistry, a solution phase combinatorial synthesis and screening of mini libraries of 1,2,4-triazole derivatives has been carried out. 6 x 6 indexed mini libraries were synthesized comprising of 36 compounds. The libraries were analyzed by liquid chromatography - mass spectrometry - mass spectrometry (LC - MS - MS) analysis. All the synthesized mini libraries were screened for antifungal activity and by deconvolution methodology leads for every fungi used for study were identified. The leads were synthesized individually and screened for activity. The antifungal activity of individually synthesized leads was improved as anticipated, in comparison with that of any of the mini libraries. Springer Science+Business Media, LLC 2010.

In the present investigation, a series of 3,6-disubstituted-l,2,4-triazolo- l,3,4-thiadiazole derivatives (6a-t) were synthesized and evaluated for their anticonvulsant activity and neurotoxicity. The structures of synthesized compounds were confirmed on the basis of their elemental analysis and spectral data results. In anti- MES activity compounds 6b, 6c, 6g, 6j, 6k, 6q and 6r showed potent activity comparable to that of standard drugs: phenytoin and carbamazepine. Compounds 6c, 6k, 6n, 6p and 6s successfully passed the rotorod test without any sign of neurological deficit.

p38 MAP kinase has received considerable interest in the pharmaceutical industry and remains a valid and interesting target for the treatment of inflammation. To discover novel p38 inhibitors, we applied the ligand-based virtual screening technique, FieldScreen, to 1.2 million commercially available compounds. Fifty-eight diverse compounds were selected for biological analysis, using molecular field similarity to known inhibitors, while explicitly removing any structure that shared a scaffold with previously reported p38 inhibitors. Of these, 11 (19%) showed ≥20% inhibition of p38 at 10 μM. We chose to prepare analogues of two distinct chemical series resulting in a potential lead compound with pIC50 of 6.4. Modeling of SAR using FieldAlign, a ligand alignment protocol, was used to rationalize the SAR of the series of thiadiazole based inhibitors.

The reaction of (2E)-3-(1-benzofuran-2-yl)-2-propenoic acid with 4-amino-5-R-1,2,4-triazole-3-thioles has been investigated. It has been established, that 6-[(E)-2-(1-benzofuran-2-yl)ethenyl][1,2,4]triazolo[3,4-b][1, 3,4] thiadiazole were formed as the result of heterocyclization.

A series of novel complexes of 4-amino-5-benzyl-4H-1,2,4-triazole-3-thione (ABT), 5-benzyl-4-(benzylideneamino)-4H-1,2,4-triazole-3-thione (BBT), 5-benzyl-4-[(2-hydroxybenzylidene)amino]-4H-1,2,4-triazole-3-thione (HBHT) and 5-benzyl-4-[(4-methoxybenzylid

(Chemical Equation Presented) Various 4-amino-2,3-dihydro-4H-triazoles with aromatic, aliphatic and heterocyclic substituents at the C(5) position were synthesized from corresponding esters and thiocarbohydrazide. This method allows the synthesis these he

In this study appropriate hydrazide compounds, furan-2-carboxylic acid hydrazide (1) and phenylacetic acid hydrazide (2) were converted into 1,4-substituted thiosemicarbazides 4a-e and 5a-e and 4-amino-5-(furan-2-yl or benzyl)-4H-1,2,4-triazole-3-thiols 7

The reaction of thiocarbohydrazide with carboxylic acids at the melting temperature allows an improved preparation of the 5-substituted 4-amino-3-mercapto-1,2,4-triazole heterocycles. The crude 4-amino-5-mercapto-1,2,4-triazoles react easily with carboxylic acids or carboxylic acid chlorides to afford the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole ring system.

A series of novel 3,6-disubstituted 1,2,4-triazolo[3,4-b] [1,3,4]thiadiazole derivatives was prepared and tested to evaluate their antimycotic and antibacterial activities. Anti-HIV-1 activity has also been investigated. Among the test compounds, derivatives 10a-14a and 16c showed anti-HIV-1 activity at concentrations slightly below those cytotoxic. Substitutions at 3 and 6 positions seems to be important in lowering the cytotoxicity of compounds.

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A series of s-triazolo-1,3,4-thiadiazoles (III) carrying aryl or aralkyl group at 2-position and aryl, aralkyl or diaralkyl group at 5-position have been synthesised and evaluated for their biological activities.Some of the compounds exhibit strong CNS depressant and mild to moderate antiinflammatory action in experimental animals.