- Design, synthesis and antibacterial activities of 5-(pyrazin-2-yl)-4H-1,2, 4-triazole-3-thiol derivatives containing Schiff base formation as FabH inhibitory
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A series of novel schiff base derivatives (H1-H20) containing pyrazine and triazole moiety have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of β-ketoacyl-acyl carrier protein synthase III (FabH). These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Bacillus amyloliquefaciens and selected compounds among them were tested for their Escherichia coli FabH inhibitory activity. Based on the biological data, compound H17 showed the most potent antibacterial activity with MIC values of 0.39-1.56 μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 5.2 μM, being better than the positive control Kanamycin B with IC50 of 6.3 μM. Furthermore, docking simulation was performed to position compound H17 into the E. coli FabH active site to determine the probable binding conformation. This study indicated that compound H17 has demonstrated significant E. coli FabH inhibitory activity as a potential antibacterial agent and provides valuable information for the design of E. coli FabH inhibitors.
- Zhang, Fei,Wen, Qing,Wang, She-Feng,Shahla Karim, Baloch,Yang, Yu-Shun,Liu, Jia-Jia,Zhang, Wei-Ming,Zhu, Hai-Liang
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- Design, synthesis, anti-mycobacterial and cytotoxic evaluation of C-4 functionalized 1,8-naphthalimide-heterocyclic hydrazide conjugates
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This manuscript discloses the design and synthesis of a series of C-4 functionalized 1,8-naphthalimide-heterocyclic hydrazide conjugates along with their anti-mycobacterial and cytotoxic evaluation. The present work assumes significance as it describes the first report on the amalgamation of C-4 substituted naphthalimides with various heterocyclic hydrazides. However, contrary to the rationale behind the synthesis of the conjugates, none of them inhibited the growth of Mycobacterium tuberculosis at the tested concentrations though these were non-cytotoxic towards the Vero kidney epithelial cell line.
- Shalini,Johansen, Matt D.,Kremer, Laurent,Kumar, Vipan
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- Cobalt and silver complexes of terdentate pyrazine-based amide ligands and assembly of monocobalt building blocks through a silver connector
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Two terdentate pyrazine-based amide ligands have been prepared from methyl pyrazine-2-carboxylate and 2-(amino-methyl)pyridine (HL1M) or 2- 2-aminoethyl)pyridine (HL1E) in order to probe the potential of the "spare" nitrogen atom "out: the back" of the pyrazine ring to coordinate to a different metal ion and thereby act as a linker between complexes. Two inert cobalt(III) complexes, [CoIII(L 1M)2](BF4) 1/4H2O and Co III(L1E)2](BF4)-1/2H20, have been prepared as building blocks and the silver(I) coordination of the ligands also probed, forming {[AgI(HL1M)]BF 4}∞, and [AgI2(HL1LE) 2]- (BF4)2. The [CoIII(L 1E)2](BF4) building block has been successfully connected to a second such complex by coordination of silver(I) to a "spare" pyrazine nitrogen atom on each complex, resulting in [{Co III(L1E)2}2AgI](BF 4)(N03)2, All five complexes have been structurally characterised. Mass spectra and cyclic voltammetry studies on "aged" (kept in solution in air for 2 d) samples clearly showed that the cobalt complex of the methylene-linked ligand was prone to slow ligand oxidation, forming [CoIII(L1Mox)(L1M)](BF 4) and [CoIII(L1Mox)2](BF 4). Fresh samples of [CoIII(L1M) 2](BF4)-1/4H20 and oIII(L 1M)2](BF4)-1/2H20 undergo a chemically reversible one- electron reduction in dry acetonitrile, at -0.71 and -0.48 V vs. 0.01 M AgN03/Ag, respectively, consistent with the methylene-linked ligand being better able to stabilise the higher oxidation state of cobalt than the ethylene-linked ligand.
- Hellyer, Ryan M.,Larsen, David S.,Brooker, Sally
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- Evaluation and Docking Study of Pyrazine Containing 1, 3, 4-Oxadiazoles Clubbed with Substituted Azetidin-2-one: A New Class of Potential Antimicrobial and Antitubercular
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Background Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the main killers of people all over the world. The major hurdles with existing therapy are the lengthy regimen and appearance of multi drug resistant (MDR) and extensively drug resistant (XDR) strains of M.tuberculosis. Aims The present work was aimed to synthesize and determine antitubercular and antimicrobial potential of some novel 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl[1,3,4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7 (a - h) from pyrazinoic acid as precursor, which is a well-established antitubercular agent. Here we report the synthesis of a new class of heterocyclic molecules in which pyrazine, 1, 3, 4-oxadiazole and azetidinone moieties were present in one frame work. Methods Pyrazinoic acid (1) was esterified first (2) followed by amination to produce hydrazide (3) which was refluxed with POCl3 to obtain 2-chloromethyl-5pyrazino-1, 3, 4-oxadiazole (4). This was then further reacted with 4-amino phenol to obtain 4-[5-pyrazino-1, 3, 4-oxadiazol-2-yl-methoxy]-phenyl amine (5) which on condensation with various aromatic aldehydes afforded a series Schiff's bases 6(a-h). Dehydrative annulations of 6(a-h) in the presence of chloroacetyl chloride and triethylamine yielded 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl-[1, 3, 4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(a-h). Antibacterial, antifungal and antitubercular potential of all the synthesized compounds were assessed. Docking study was performed using the software VLife Engine tools of Vlifemds 4.6 on the protein lumazine synthase of M. tuberculosis (PDB entry code 2C92). Results The present studies demonstrated that synthesized oxadiazole derivatives have good antimicrobial activity against the various microorganisms. Among the synthesized derivative, 7b and 7g were found to be prominent compounds which have potential antibacterial, antifungal and antitubercular activity (with MIC 3.12 μg/ml and high dock score ranging from -59.0 to -54.0) against Mycobacterium tuberculosis. Conclusions Derivatives 7b and 7g would be effective lead candidates for tuberculosis therapy.
- Das, Rina,Mehta, Dinesh Kumar
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- A chromone hydrazide Schiff base fluorescence probe with high selectivity and sensitivity for the detection and discrimination of human serum albumin (HSA) and bovine serum albumin (BSA)
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The discrimination and identification of human serum albumin (HSA) and bovine serum albumin (BSA) is very important, which is due to the vital roles of two SAs in biological and pharmaceutical research. Based on structural screening and docking calculation from a series of homologues, a coumarin Schiff base fluorescent probe 3-hydroxy-N′-((4-oxo-4H-chromen-3-yl)methylene)-2-naphthohydrazide (HCNH) has been designed and synthesized, which could effectively discriminate HSA and BSA. The probe HCNH exhibited superior sensitivity toward HSA and BSA with the detection limits of 10.62 nM and 16.03 nM in PBS solution, respectively. The binding mechanism of HCNH with SAs was studied by Job's plot analysis, SA destruction and displacement assay. Molecular docking and DFT methods were utilized to provide deep insight into the spatial conformation change of HCNH and binding sites in HSA/BSA. The conformation of HCNH was significantly influenced by the microenvironment provided by HSA and BSA, therefore its fluorescence emission was affected correspondingly. Non-toxic probe HCNH could be successfully used for fluorescence bio-imaging of HSA in cancer cells, which is significantly different from normal cells and favors the application in medical diagnosis.
- Fan, Jing,Li, Qing-Zhong,Li, Zhe,Liu, Hai-Bo,Wang, Zhi-Gang,Xie, Cheng-Zhi,Xu, Jing-Yuan,Yan, Xiao-Jing
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- New silver(I) phosphino complexes: Evaluation of their potential as prospective agents against Mycobacterium tuberculosis
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Despite being a preventable and curable disease, Tuberculosis (TB) is the world's top infectious killer. Development of new drugs is urgently needed. In this work, the synthesis and characterization of new silver(I) complexes, that include N′-[(E)-(pyridine-2-ylmethylene)pyrazine-2-carbohydrazide, HPCPH, as main ligand and substituted aryl-phosphines as auxiliary ligands, is reported. HPCPH was synthesized from pyrazinoic acid, the active metabolite of the first-line antimycobacterial drug pyrazinamide. Complexes [Ag(HPCPH)(PPh3)2]OTf (1), [Ag(HPCPH)((P(p-tolyl)3)2]OTf (2) and [Ag(HPCPH)(P(p-anisyl)3)2]OTf (3) were characterized in solid state and in solution by elemental analysis and FTIR and NMR spectroscopies (OTf[dbnd]triflate). Crystal structures of (1,2) were determined by XRD. The Ag atom is coordinated to azomethine and pyridine nitrogen atoms of HPCPH ligand and to the phosphorous atom of each aryl-phosphine co-ligand. Although HPCPH did not show activity, the Ag(I) compounds demonstrated activity against Mycobacterium tuberculosis (MTB), H37Rv strain, and multi-drug resistant clinical isolates (MDR-TB). Globally, results showed that the compounds are not only effective against the sensitive strain, but are more potent against MDR-TB than antimycobacterial drugs used in therapy. The compounds showed low to moderate selectivity index values (SI) towards the bacteria, using MRC-5 cells (ATCC CCL-171) as mammalian cell model. Interaction with DNA was explored to get insight into the potential mechanism of action against the pathogen. No significant interaction was detected, allowing to discard this biomolecule as a potential molecular target. Compound 1 was identified as a hit compound (MIC90 2.23 μM; SI 4.4) to develop further chemical modifications in the search for new drugs.
- Gambino, Dinorah,Maldonado, Yndira Dolores,Manieri, Karyn Fernanda,Pavan, Fernando R.,Scalese, Gonzalo,Aguirre Méndez, Larry D.
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- Highly chemoselective deoxygenation of N-heterocyclic: N -oxides under transition metal-free conditions
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Because their site-selective C-H functionalizations are now considered one of the most useful tools for synthesizing various N-heterocyclic compounds, the highly chemoselective deoxygenation of densely functionalized N-heterocyclic N-oxides has received much attention from the synthetic chemistry community. Here, we provide a protocol for the highly chemoselective deoxygenation of various functionalized N-oxides under visible light-mediated photoredox conditions with Na2-eosin Y as an organophotocatalyst. Mechanistic studies imply that the excited state of the organophotocatalyst is reductively quenched by Hantzsch esters. This operationally simple technique tolerates a wide range of functional groups and allows high-yield, multigram-scale deoxygenation. This journal is
- Kim, Se Hyun,An, Ju Hyeon,Lee, Jun Hee
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supporting information
p. 3735 - 3742
(2021/05/04)
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- PIEZO1 AGONISTS FOR THE PROMOTION OF BONE FORMATION
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Disclosed herein are Piezo 1 agonists. Also disclosed herein are methods of stimulating tissue anabolism in a subject comprising administering an effective amount of a Piezo 1 agonist and methods for chemically mimicking mechanical stimulation of a cell expressing Piezo 1 comprising contacting a cell expressing Piezo1 with an effective amount of a Piezo 1 agonist.
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Page/Page column 30; 32
(2021/04/10)
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- 1H-1,2,3-triazole embedded Isatin-Benzaldehyde-bis(heteronuclearhydrazones): design, synthesis, antimycobacterial, and cytotoxic evaluation
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Rapid growth of global drug-resistant tuberculosis and urgent requirement for short treatment regimens is stimulating the need for discovery of new TB drugs. In this work, we report the design, synthesis and in vitro antimycobacterial evaluation of a library of isatin-derived bis(heteronuclear hydrazones). Evaluation results revealed that the inclusion of isoniazid core into 1H-1,2,3-triazole tethered isatin-benzaldehydes improved the antimycobacterial activity on tuberculosis mc26230 strain and significantly reduced the cytotoxicity against Vero cells. However, the introduction of semicarbazones/thiosemicarbazones or pyrazine-2-carbohydrazide produced the opposite effects. The compounds with isoniazid and polar-donating groups at the C-5 position of isatin emerged as the most promising conjugates with MIC99?=?0.36?μg/ml. The most active compounds were non-cytotoxic to Vero cells (IC50>100?μg/ml) with selectivity indices >277.
- Johansen, Matt D.,Kremer, Laurent,Kumar, Sumit,Kumar, Vipan,Preeti,Sharma, Bharvi
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- N-acylhydrazones confer inhibitory efficacy against New Delhi metallo-β-lactamase-1
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The expression of β-lactamases, especially metallo-β-lactamases (MβLs) in bacteria is one of the main causes of drug resistance. In this work, an effective N-acylhydrazone scaffold as MβL inhibitor was constructed and characterized. The biological activity assays indicated that the synthesized N-acylhydrazones 1–11 preferentially inhibited MβL NDM-1, and 1 was found to be the most effective inhibitor with an IC50 of 1.2 μM. Analysis of IC50 data revealed a structure–activity relationship, which is that the pyridine and hydroxylbenzene substituents at 2-position improved inhibition of the compounds on NDM-1. ITC and enzyme kinetics assays suggested that it reversibly and competitively inhibited NDM-1 (Ki = 0.29 ± 0.05 μM). The synthesized N-acylhydrazones showed synergistic antibacterial activities with meropenem, reduced 4–16-fold MIC of meropenem on NDM-1- producing E. coli BL21 (DE3), while 1 restored 4-fold activity of meropenem on K. pneumonia expressing NDM-1 (NDM-K. pneumoniae). The mice experiments suggested that 1 combined meropenem to fight against NDM-K. pneumoniae infection in the spleen and liver. Cytotoxicity assays showed that 1 and 2 have low cytotoxicity. This study offered a new framework for the development of NDM-1 inhibitors.
- Gao, Han,Li, Jia-Qi,Kang, Peng-Wei,Chigan, Jia-Zhu,Wang, Huan,Liu, Lu,Xu, Yin-Sui,Zhai, Le,Yang, Ke-Wu
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- A novel hydrazide Schiff base self-assembled nanoprobe for selective detection of human serum albumin and its applications in renal disease surveillance
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Human serum albumin (HSA) is considered as a biomarker for the early diagnosis of renal disease, therefore identifying and detecting HSA in biological fluids (especially urine) with an easy method is of great importance. Herein, we report a novel hydrazide Schiff base fluorescent probe N′-((7-(diethylamino)-2-oxo-2H-chromen-3-yl)methylene)pyrazine-2-carbohydrazide (NPC), which self-assembled into nanoparticles in aqueous solution. Based on disassembly-induced emission and the site-specific recognition mechanism, the binding of NPC with HSA resulted in a fluorescence "turn-on"response. Probe NPC exhibited superior selectivity and sensitivity toward HSA with a detection limit of 0.59 mg L-1 in PBS and 0.56 mg L-1 in the urine sample. The site-binding mechanism of NPC with HSA was explored by fluorescence quenching study, Job's plot analysis, HSA destruction, site marker displacement and molecular docking. Fluorescence imaging of HSA in MCF-7 cells was achieved by using a non-toxic NPC probe, suggesting that NPC could be applied to visualize the level of HSA in vivo. More importantly, further practical applications of probe NPC in human urine samples were achieved with satisfactory results by using a fluorometer or test paper, which could provide extensive application in clinical diagnosis.
- Li, Qing-Zhong,Liu, Hai-Bo,Liu, Wei,Wang, Zhi-Gang,Xie, Cheng-Zhi,Xu, Jing-Yuan,Yan, Xiao-Jing,Zhang, De-Long
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p. 8346 - 8355
(2020/10/06)
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- Continuous-Flow Pd-Catalyzed Carbonylation of Aryl Chlorides with Carbon Monoxide at Elevated Temperature and Pressure
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The development of a continuous-flow protocol for a palladium-catalyzed methoxycarbonylation of (hetero)aryl chlorides using carbon monoxide gas and methanol is described. (Hetero)aryl chlorides are the least expensive of the aryl halides, but are underutilized in carbonylation reactions due to their very poor reactivity. The described protocol exploits intensified conditions at elevated temperature and pressure, which are readily accessed within a continuous-flow environment, to provide moderate to excellent product yields (11 examples) in a short 16 min residence time. The continuous-flow protocol enables the safe and potentially scalable carbonylation of aryl chlorides using CO gas.
- Mata, Alejandro,Hone, Christopher A.,Gutmann, Bernhard,Moens, Luc,Kappe, C. Oliver
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p. 997 - 1001
(2019/01/24)
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- Application of self-assembled nano fluorescent probe for selective detection of human serum albumin
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The invention discloses a novel self-assembled nanoparticle formed by a hydrazide Schiff base and used as a fluorescent probe. The hydrazide Schiff base is self-assembled into a nano system in a PBS buffer, and the nano system can be used for qualitative and quantitative detection of human serum albumin (HSA). The advantage of the probe is that: based on a mechanism of self-assembly and twisted intramolecular charge transfer, the probe itself has almost no fluorescence signal, and has obvious fluorescence enhancement after interaction with a substance to be detected. A synthesis route of the probe is simple and convenient, yield is high, the nano system is formed uniformly and fast by self-assembly, selectivity of a substance to be detected is good, and sensitivity is high. The self-assembled nano fluorescent probe can be used for detecting HSA in biological and clinical test samples, and has good application prospects.
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Paragraph 0010; 0017
(2019/11/12)
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- Targeted structural modification of spin crossover complexes: pyridine vs pyrazine
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2-(Aminomethyl)pyrazine has been prepared in five steps from 2-pyrazine carboxylic acid. From this key amine, two new bis-terdentate triazole-based ligands which feature pendant pyrazine groups, PZMAT and PZMPT (4-amino- and 4-pyrrolyl-3,5-bis{[(2-pyrazylmethyl)amino]methyl}-4H-1,2,4-triazole, respectively), and two dinuclear complexes of them, [FeII 2(PZMAT)2](BF4)4?MeOH?2H2O (1?MeOH?2H2O) and [FeII 2(PZMPT)2](BF4)4?3H2O (2?3H2O), have been prepared. A structure determination at 100?K on 2?3.5MeCN confirmed that the ligands adopt the expected binding mode, providing all twelve donors to the two iron(II) centres and two N1,N2-triazole bridges between them. Both undergo gradual incomplete spin transitions: at room temperature 1?MeOH?2H2O and 2?3H2O are approximately two-thirds to three-quarters [HS-HS], dropping to mostly ‘[HS-LS]’ at 50?K. The structure determination and M?ssbauer spectroscopy of 2 qualitatively support this. These findings are consistent with the pendant pyrazines providing a somewhat higher field strength than the pendant pyridines do in the analogous PMRT complexes.
- Feltham, Humphrey L. C.,Cowan, Matthew G.,Kitchen, Jonathan A.,Jameson, Guy N. L.,Brooker, Sally
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p. 296 - 304
(2017/09/06)
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- Design, Synthesis and Evaluation of Antitubercular Activity of Novel 1,2,4-Triazoles Against MDR Strain of Mycobacterium tuberculosis
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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.
- Ganesh Kumar,Gautham Shenoy,Kar, Sidhartha Sankar,Shenoy, Vishnu,Bairy, Indira
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p. 907 - 917
(2018/02/07)
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- NOVEL CLOSTRIDIUM DIFFICILE TOXIN INHIBITORS
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The present invention relates to benzodiazepine derivative compounds of formula (I), or pharmaceutically acceptable salts thereof. The present benzodiazepine compounds are useful Clostridium difficile inhibitors in the treatment of Clostridium difficile infection in humans. The present invention provides a pharmaceutical composition containing benzodiazepine compounds of formula (I) and a method of making as well as a method of using the same in treating patients infected with Clostridium difficile infection by administering the same. The compounds of the present invention may be used in combination with additional antibiotics or anti-toxin antibody drugs.
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(2018/01/17)
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- Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes
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Isonicotinyl and pyrazinyl ferrocenyl-derived complexes were prepared using various hydrazides and ferrocenyl aldehydes. Three heterobimetallic complexes were also synthesized from the Schiff base-derived isonicotinyl ferrocene complex using various platinum group metal dimers based on ruthenium, rhodium and iridium. All complexes were evaluated in vitro for antimycobacterial and antiparasitic activity. Against Mycobacterium tuberculosis H37Rv, the platinum group metal complexes showed glycerol-dependent antimycobacterial activity. The antiplasmodial activities against the NF54 chloroquine-sensitive strain of Plasmodium falciparum of some compounds were moderate, while some complexes also showed promising activity against Trichomonas vaginalis. Incorporation of the ferrocenyl-salicylaldimine moiety resulted in enhanced antimicrobial activity compared to the non-ferrocenyl compound in some cases. The bimetallic iridium-ferrocene isonicotinyl complex exhibited superior antitrichomonal activity relative to its organic counterpart, isoniazid. Furthermore, all these compounds, when screened on several normal flora bacteria of humans, showed no effect on the microbiome, emphasizing the selection of these compounds for these pathogens. The promising antimicrobial activities of the complexes thus supports incorporation of ferrocene as part of existing antimicrobial therapies in order to alter their biological activities favorably.
- Stringer, Tameryn,Seldon, Ronnett,Liu, Nicole,Warner, Digby F.,Tam, Christina,Cheng, Luisa W.,Land, Kirkwood M.,Smith, Peter J.,Chibale, Kelly,Smith, Gregory S.
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p. 9875 - 9885
(2017/08/09)
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- Synthesis and biological evaluation of 1,2-dithiol-3-thiones and pyrrolo[1,2-a]pyrazines as novel hypoxia inducible factor-1 (HIF-1) inhibitor
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Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor which is strongly associated with tumor survival, progression, and therapeutic resistance. Accordingly, it has been suggested that the inhibition of the HIF-1 pathway can suppress tumor, and it has become an important therapeutic target. In present study, oltipraz, its metabolite M2, and their derivatives were synthesized and evaluated as HIF-1α inhibitors. Among the synthesized, benzyl-substituted pyrrolo[1,2-a]pyrazine 2g most potently inhibited HIF-1α protein accumulation (81% at 10 μM) and VEGF, GLUT-1 transcription (77% and 92% at 10 μM, respectively).
- Lee, Young Hun,Lee, Jung Min,Kim, Sang Geon,Lee, Yong Sup
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p. 2843 - 2851
(2016/06/08)
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- METHODS FOR PREPARING OLTIPRAZ
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The invention provides improved methods of synthesizing oltipraz, which result in higher overall yield and better purity of the desired product.
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Page/Page column 3; 13; 14
(2017/01/09)
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- Synthesis and biological evaluation of novel resveratrol-oxadiazole hybrid heterocycles as potential antiproliferative agents
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A novel class of resveratrol-oxadiazole hybrid compounds was synthesized to screen for their in vitro antiproliferative activity against three human cancer cell lines. All the compounds showed superior antiproliferative activity than the reference compound resveratrol. The most promising active compounds in this series were 1g, 2g, 1c, 2c, 2i and 1a (GI50 0.1 μM), endowed with excellent antiproliferative activity. Thus, we believe that resveratrol-oxadiazole hybrid compounds may possibly be used as a good leads for the development of new antiproliferative agents. Structures of newly synthesized compounds were confirmed by NMR and IR spectral data.
- Murty,Penthala, Raju,Polepalli, Sowjanya,Jain
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p. 627 - 643
(2016/03/08)
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- Salicylanilide pyrazinoates inhibit in vitro multidrug-resistant Mycobacterium tuberculosis strains, atypical mycobacteria and isocitrate lyase
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The development of antimicrobial agents represents an up-to-date topic. This study investigated in vitro antimycobacterial activity, mycobacterial isocitrate lyase inhibition and cytotoxicity of salicylanilide pyrazinoates. They may be considered being mutual prodrugs of both antimycobacterial active salicylanilides and pyrazinoic acid (POA), an active metabolite of pyrazinamide, in which these esters are likely hydrolysed without presence of pyrazinamidase/nicotinamidase. Minimum inhibitory concentrations (MICs) of the esters were within the range 0.5-8 μmol/l for Mycobacterium tuberculosis and 1-32 μmol/l for nontuberculous mycobacteria (Mycobacterium avium, Mycobacterium kansasii). All esters showed a weak inhibition (8-17%) of isocitrate lyase at the concentration of 10 μmol/l. The most active pyrazinoates showed MICs for multidrug-resistant tuberculosis strains in the range of 0.125-2 μmol/l and no cross-resistance with clinically used drugs, thus being the most in vitro efficacious salicylanilide esters with 4-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate superiority (MICs ≤ 0.25 μmol/l). This promising activity is likely due to an additive or synergistic effect of released POA and salicylanilides. Selectivity indexes for the most active salicylanilide pyrazinoates ranged up to 64, making some derivatives being attractive candidates for the next research; 4-bromo-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate showed the most convenient toxicity profile.
- Krátky, Martin,Vin?ová, Jarmila,Novotná, Eva,Stola?íková, Ji?ina
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.
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Paragraph 0535; 0536
(2013/10/08)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including CNS or neurodegeneration disorder.
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Page/Page column 89-90
(2012/04/10)
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- Design, synthesis and biological evaluation of heterocyclic azoles derivatives containing pyrazine moiety as potential telomerase inhibitors
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Three series of novel heterocyclic azoles derivatives containing pyrazine (5a-5k, 8a-8k and 11a-11k) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential telomerase inhibitors. Among the oxadiazole derivatives, compound 5c showed the most potent biological activity against SW1116 cancer cell line (IC50 = 2.46 μM against SW1116 and IC50 = 3.55 μM for telomerase). Compound 8h performed the best in the thiadiazole derivatives (IC50 = 0.78 μM against HEPG2 and IC50 = 1.24 μM for telomerase), which was comparable to the positive control. While compound 11f showed the most potent biological activity (IC50 = 4.12 μM against SW1116 and IC50 = 15.03 μM for telomerase) among the triazole derivatives. Docking simulation by positioning compounds 5c, 8h and 11f into the telomerase structure active site was performed to explore the possible binding model. The results of apoptosis demonstrated that compound 8h possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 8h with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. Therefore, the introduction of oxadiazole, thiadiazole and triazole structures reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity.
- Zhang, Yan-Bin,Wang, Xiao-Liang,Liu, Wen,Yang, Yu-Shun,Tang, Jian-Feng,Zhu, Hai-Liang
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p. 6356 - 6365
(2012/11/07)
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- Synthesis and antitubercular evaluation of N-Arylpyrazine and N,Na-Alkyl-diylpyrazine-2-carboxamide derivatives
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Two series of pyrazinamide (PZA) derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Some compounds exhibited minimum inhibitory concentration activity of 50-100 μg/mL, greater than the first line antituberculosis drug PZA in Alamar Blue assay (>100 μg/mL). The obtained activities can be considered promising results, which characterizes these compounds as good start points to development of new antitubercular agents.
- Bispo, Marcelle De Lima Ferreira,Goncalves, Raoni Schroeder Borges,Lima, Camilo Henrique Da Silva,Cardoso, Laura Nogueira De Faria,Lourenco, Maria Cristina Silva,De Souza, Marcus Vinicius Nora
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p. 1317 - 1322
(2013/02/22)
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- KYNURENINE PRODUCTION INHIBITOR
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Provided is a kynurenine production inhibitor comprising a nitrogen-containing heterocyclic compound represented by formula (I): (wherein R50 and R51 may be the same or different and each represent a hydrogen atom or the like, G1 and G2 may be the same or different and each represent a nitrogen atom or the like, X represents formula (III): (wherein m1 and m2 may be the same or different and each represent an integer of 0 or 1, Y represents an oxygen atom or the like, and R6 and R7 may be the same or different and each represent a hydrogen atom or the like), R1 represents optionally substituted lower alkyl or the like, R2 represents a hydrogen atom or the like, and R3 represents optionally substituted lower alkyl or the like), and the like.
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Page/Page column 132
(2011/10/12)
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- Dinuclear, tetranuclear and chain (MnII, CoII) complexes of multifunctional hydrazone ligands- Structural and magnetic studies
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The coordination chemistry of a group of hydrazone-based ligands, modified with carboxylate and heterocyclic terminal donor groups, with MnII and CoII has been investigated. The multifunctional nature of the ligands allows coordinative flexibility based on the hydrazone core, which is well established to lead to spin-coupled polymetallic assemblies through μ-Ohydrazone bridging. Examples of dinuclear, tetranuclear and chain complexes are reported with hydrazone, carboxylate and triazole bridging. Spin exchange through the μ-O and μ-N,N bridging connections leads to antiferromagnetic exchange in most cases, except for the central subunit in the MnII4 chain complex, where small ( 90°) bridge angles result in contributing ferromagnetic interactions. Multifunctional polytopic hydrazone ligands form polymetallic complexes with μ-O (hydrazone, carboxylate) and μ-N,N (triazole) bridging, leading to spin-spin interactions between the metal centres with examples of antiferromagnetic and ferromagnetic exchange.
- Bettle, Peter J.,Dawe, Louise N.,Anwar, Muhammad U.,Thompson, Laurence K.
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experimental part
p. 5036 - 5042
(2012/01/14)
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- 5,6,7,8-TETRAHYDRO[1,2,4]TRIAZOLO[4,3-a]PYRAZINE DERIVATIVES AS P2X7 MODULATORS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein A is hydrogen, C1-4alkyl, C3-6cycloalkyl, C1-3alkoxy, C1-3alkoxy C1-4alkyl, C1-2fluoroalkyl, halogen, NR6 R7, optionally substituted heteroaryl (Het), or optionally substituted phenyl, and R1, R2, R3, R4, R5, R6 and R7 are as defined in the description. The compounds or salts are thought to modulate P2X7 receptor function and to be capable of antagonizing the effects of ATP at the P2X7 receptor. The invention also provides the use of the compound or salt in the treatment or prophylaxis of, for example, inflammatory pain, neuropathic pain, visceral pain, rheumatoid arthritis, osteoarthritis or neurodegenerative disorders.
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Page/Page column 125
(2010/11/17)
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- Synthesis and cytotoxic evaluation of disubstituted N-acylhydrazones pyrazinecarbohydrazide derivatives
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A series of seventeen disubstituted N-acylhydrazone pyrazinecarbohydrazide (4-20) have been synthesized and evaluated for their cell viabilities, were compared to another monosubstituted derivatives previously synthesized by us. This study indicated that the position and nature of the substituents in the aromatic ring influence the cytotoxicity of this series.
- De Ferreira, Marcelle L.,Candea, Andre L. P.,Henriques, Maria Das Gracas M. De O.,Kaiser, Carlos R.,Lima, Camilo H. Da S.,De Souza, Marcus V. N.
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scheme or table
p. 275 - 280
(2011/03/18)
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- Synthesis andanti-mycobacterial evaluation of some pyrazine-2-carboxylic acid hydrazide derivatives
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A series of pyrazine-2-carboxylic acid hydrazide derivatives were synthesized and screened for their activity against Mycobacterium tuberculosis. The results show that pyrazine-2-carboxylic acid hydrazi-deehydrazone derivatives 3ael were less active than pyrazinamide. In contrast,the N 4-ethyl-N1-pyr-azinoyl-thiosemicarbazide 4 showed the highest activity against M. tuberculosis H37Rv (IC90 16.87 mg/mL). Details of the structureeactivity and structureecytotoxicity relationships are discussed.
- Abdel-Aziz, Mohamed,Bdel-Rahman, Hamdy M.A.
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experimental part
p. 3384 - 3388
(2010/08/13)
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- 2,3,5,6-Tetra(pyrazin-2-yl)pyrazine: a novel bis-bidentate, bis-tridentate chelator
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Novel 10-nitrogen ligand, 2,3,5,6-tetra(pyrazin-2-yl)pyrazine, has been synthesized in four steps. This compound shows different conformations and the crystal structure of one of them has been established. This structure is sustained by non-classical H-bonds and π···π interactions among heteroaromatic rings.
- Ligiero, Carolina B.P.,Visentin, Lorenzo C.,Giacomini, Rosana,Filgueiras, Carlos A.L.,Miranda, Paulo C.M.L.
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supporting information; experimental part
p. 4030 - 4032
(2009/11/30)
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- Synthesis and antimycobacterial activity of N′-[(E)-(monosubstituted-benzylidene)]-2-pyrazinecarbohydrazide derivatives
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The present article describes a series of twenty-six N′-[(E)-(monosubstituted-benzylidene)]-2-pyrazinecarbohydrazide (4-29), which were synthesized and evaluated for their cell viabilities in non infected and infected macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). Afterwards, the non-cytotoxic compounds (4, 6, 8, 15, 21, 23, 24, 27 and 28) were assessed against Mycobacterium tuberculosis ATCC 27294 using the micro plate Alamar Blue assay (MABA) and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. The compounds 6, 23, 27 and 28 exhibited a significant activity (50-100 μg/mL) when compared with first line drugs such as pyrazinamide and were not cytotoxic in their respective MIC values.
- Vergara, Fatima M.F.,Lima, Camilo H. da S.,Henriques, Maria das Gracas M. de O.,Candea, Andre L.P.,Lourenco, Maria C.S.,Ferreira, Marcelle de L.,Kaiser, Carlos R.,de Souza, Marcus V.N.
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experimental part
p. 4954 - 4959
(2010/02/27)
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- Novel Isoxazoles and Methods of Use Thereof
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The invention relates to isoxazole derivatives, compositions comprising such compounds, and methods of preventing or treating conditions and disorders using such compounds and compositions.
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Page/Page column 19
(2009/12/24)
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- Rhodanineacetic acid derivatives as potential drugs: Preparation, hydrophobic properties and antifungal activity of (5-arylalkylidene-4-oxo-2- thioxo-1,3-thiazolidin-3-yl)acetic acids
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Some [(5Z)-(5-arylalkylidene-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)]acetic acids were prepared as potential antifungal compounds. The general synthetic approach to all synthesized compounds is presented. Lipophilicity of all the discussed rhodanine-3-acetic acid derivatives was analyzed using a reversed phase high performance liquid chromatography (RP-HPLC) method. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary RP column. The RP-HPLC retention parameter log k (the logarithm of the capacity factor k) is compared with log P values calculated in silico. All compounds were evaluated for antifungal effects against selected fungal species. Most compounds exhibited no interesting activity, and only {(5Z)-[4-oxo-5-(pyridin-2- ylmethylidene)-2-thioxo-1,3-thiazolidin-3-yl]}acetic acid strongly inhibited the growth of Candida tropicalis 156, Candida krusei E 28, Candida glabrata 20/Iand Trichosporon asahii 1188.
- Dolezel, Jan,Hirsova, Petra,Opletalova, Veronika,Dohnal, Jiri,Marcela, Vejsova,Kunes, Jiri,Jampilek, Josef
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experimental part
p. 4197 - 4212
(2010/03/03)
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- Derivatives of pyrazinecarboxylic acid: 1H, 13C and 15N NMR spectroscopic investigations
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NMR spectroscopic studies are undertaken with derivatives of 2-pyrazinecarboxylic acid. Complete and unambiguous assignment of chemical shifts (1H, 13C, 15N) and coupling constants (1H,1H; 13C,1H; 15N,1H) is achieved by combined application of various 1D and 2D NMR spectroscopic techniques. Unequivocal mapping of13C,1H spin coupling constants is accomplished by 2D (S,J) long-range INEPT spectra with selective excitation. Phenomena such as the tautomerism of 3-hydroxy-2-pyrazinecarboxylic acid are discussed.
- Holzer, Wolfgang,Eller, Gernot A.,Datterl, Barbara,Habicht, Daniela
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scheme or table
p. 617 - 624
(2010/07/05)
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- MGluR5 modulators I
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The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
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Page/Page column 25-26
(2008/06/13)
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- Tandem pinacol coupling-rearrangement of aromatic aldehydes with hydrogen catalyzed by a combination of a platinum complex and a polyoxometalate
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Together with a strongly oxidizing polyoxometalate, H5PV 2Mo10O40, PtII(N-(2,6- diisopropylphenyl)pyrazin-2-ylmethanimine)Cl2 forms a combined catalyst that was active in the tandem pinacol coupling-rearrangement of aryl aldehydes to give mostly the corresponding diarylacetaldehyde in high yields using molecular hydrogen as the reducing agent. The Royal Society of Chemistry.
- Branytska, Olena,Shimon, Linda J. W.,Neumann, Ronny
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p. 3957 - 3959
(2008/10/09)
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- Experimental thermochemical study of three monosubstituted pyrazines
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The standard (p° = 0.1 MPa) molar enthalpies of formation of liquid pyrazinecarbonitrile and of crystalline pyrazinecarboxylic acid and pyrazinamide were measured, at T= 298.15 K, by static bomb calorimetry and the standard molar enthalpies of vaporization or of sublimation, at T= 298.15 K, were obtained using Calvet microcalorimetry. These values were used to derive the respective standard molar enthalpies of formation in gaseous phase.
- Ribeiro Da Silva, Maria D. M. C.,Miranda, Margarida S.,Vaz, Claudia M. V.,Matos, M. Agostinha R.,Acree Jr.
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- ANTIFUNGAL AGENTS
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Compounds of formula (I), and pharmaceutically acceptable salts thereof, may be used in therapy, for example as antifungal agents, wherein: R1, R2 and R3 are as defined herein. Certain compounds of formula (I) are also provided. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.
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Page/Page column 39
(2010/02/14)
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- Dithiolthione compounds for the treatment of neurological disorders and for memory enhancement
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The invention provides methods to treat neurological disorders such as Alzheimer's disease, or to slow the progression of such diseases, or to treat and/or prevent other disorders as disclosed in the specification, by administering to patients, or delivering to the tissues of such patients, oltipraz or related compounds as disclosed in the specification.
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- Improved carbonylation of heterocyclic chlorides and electronically challenging aryl bromides
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Optimized conditions are described that effect the carbonylation of diverse heterocyclic chlorides to yield the desired alkyl esters. In addition, bromoanilines and bromoanisoles, which normally are poor substrates under standard carbonylation protocols, were efficiently converted to the desired products under these new conditions. The nature of the metal bidentate ligand complex was found to be critical. Specifically, a correlation between ligand bite angle and catalytic efficiency is documented.
- Albaneze-Walker, Jennifer,Bazaral, Charles,Leavey, Tanya,Dormer, Peter G.,Murry, Jerry A.
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p. 2097 - 2100
(2007/10/03)
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- METHOD FOR PREPARING OLTIPRAZ
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Provided is a method for preparing oltipraz. The method includes reacting methyl 2-methyl-3-(pyrazin-2-yl)-3-oxopropionate with phosphorus pentasulfide in the presence of a mixed solvent of toluene and xylene, followed by recrystallization.
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- New isoxazole derivatives designed as nicotinic acetylcholine receptor ligand candidates
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In this work we report the synthesis and evaluation of the analgesic properties of new isosteric heterocyclic derivatives, presenting the isoxazole nucleus, designed as nicotinic acetylcholine receptor ligand candidates, analogues to alkaloid epibatidine. Compound 2-(3-methyl-5-isoxazolyl)pyridine (3) presented the best analgesic profile of this series in hot plate test, which was partially prevented by pretreatment with nicotinic receptor antagonist mecamylamine.
- Silva, Nilda M,Tributino, Jorge L.M,Miranda, Ana L.P,Barreiro, Eliezer J,Fraga, Carlos A.M
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p. 163 - 170
(2007/10/03)
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- Process for the preparation of optically active piperazine-2-carboxylic acid derivatives
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Optically active piperazine-2-carboxylic acid derivatives of the general formula: STR1 in which X is alkoxy or a (substituted) amino group, are prepared by asymmetric hydrogenation of the corresponding pyrazinecarboxylic acid derivatives, catalyzed by optically active rhodium complexes. The compounds of the formula I are intermediates for the preparation of pharmaceutical active substances, for example, HIV protease inhibitors.
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- Process for the preparation of optically active piperazine-2-carboxylic acid derivatives
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Optically active piperazine-2-carboxylic acid derivatives of the general formula: STR1 wherein R1 and R2 are inter alia hydrogen, alkyl or acyl and X is alkoxy or a (substituted) amino group, are prepared by asymmetric hydrogenation of the corresponding 1,4,5,6-tetrahydropyrazines, catalyzed by optically active rhodium, ruthenium or iridium complexes. The compounds of the Formula 1 are intermediates for the preparation of pharmaceutical active ingredients, for example, HIV protease inhibitors.
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- Pyrazinoic Acid Esters with Broad Spectrum in Vitro Antimycobacterial Activity
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A series of substituted pyrazinoic acid esters has been prepared and examined for their in vitro activity against Mycobacterium avium and Mycobacterium kansasii as well as mycobacterium tuberculosis.Modification of both the pyrazine nucleus and the ester functionality have been very successfull in expanding the activity of pyrazinamide to include M. avium and M. kansasii, organisms normally not susceptible to pyrazinamide.Several of these compounds have activities 100-1000-fold greater than that of pyrazinamide against M. tuberculosis.
- Cynamon, Michael H.,Gimi, Rayomand,Gyenes, Ferenc,Sharpe, Cindy A.,Bergmann, Kathryn E.,et al.
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p. 3902 - 3907
(2007/10/02)
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- A Novel Convenient and Selective Alkoxycarbonylation of Heteroaromatic Bases by Oxalic Acid Monoesters
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Methoxy- and ethoxycarbonyl radicals were easily produced by silver-catalyzed decarboxylation of methyl and ethyl esters of oxalic acid by S2O8(2-).They were utilized for the alkoxycarbonylation of heteroaromatic bases with high yield and selectivity in a two-phase system, suitable for practical applications.
- Coppa, Fausta,Fontana, Francesca,Lazzarini, Edoardo,Minisci, Francesco,Pianese, Guiseppe,Zhao, Lihua
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p. 3057 - 3060
(2007/10/02)
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