1,2,3-Triazole incorporated coumarin derivatives as potential antifungal and antioxidant agents

A series of novel ethyl-7-((1-(benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-oxo-2H-chromene-3-carboxylates 8a-h as potential antifungal agents were synthesized via click chemistry. The antifungal activity was evaluated against five human pathogenic fungal strains, such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger and Cryptococcus neoformans. Compound 8c, 8d, 8e and 8h were found to be equipotent against C. albicans when compared with miconazole and compound 8f was found to be two-fold more active compared with miconazole and equipotent to fluconazole against C. albicans. The coumarin-based triazole derivatives were also evaluated for antioxidant activity and compound 8a was found to be potent antioxidant when compared with standard drug. Furthermore, molecular docking study of the newly synthesized compounds was performed and results showed good binding mode in the active site of fungal C. albicans enzyme P450 cytochrome lanosterol 14α-emethylase. Moreover, the synthesized compounds were also analyzed for ADME properties and showed potential to build up as good oral drug candidates.     

Synthesis of novel 5-substituted pyrazole derivatives as cannabinoid antagonists

A facile seven-step sequence was developed from 4′-bromopropiophenone, utilizing a Suzuki-type coupling with an alkene, to give several novel 5-substituted pyrazole derivatives in overall yields of 11-31%. They are potent CB1 antagonists and have binding affinities similar to SR 141716A. Like SR 141716A, they may prove to be clinically useful for the treatment of obesity.     

Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists

The cannabinoid CB(2) receptor is known to modulate osteoclast function by poorly understood mechanisms. Here, we report that the natural biphenyl neolignan 4'-O-methylhonokiol (MH) is a CB(2) receptor-selective antiosteoclastogenic lead structure (K(i)?< 50?nM). Intriguingly, MH triggers a simultaneous G(i) inverse agonist response and a strong CB(2) receptor-dependent increase in intracellular calcium. The most active inverse agonists from a library of MH derivatives inhibited osteoclastogenesis in RANK ligand-stimulated RAW264.7 cells and primary human macrophages. Moreover, these ligands potently inhibited the osteoclastogenic action of endocannabinoids. Our data show that CB(2) receptor-mediated cAMP formation, but not intracellular calcium, is crucially involved in the regulation of osteoclastogenesis, primarily by inhibiting macrophage chemotaxis and TNF-α expression. MH is an easily accessible CB(2) receptor-selective scaffold that exhibits a novel type of functional heterogeneity.     

Tyrosol 1,2,3-triazole analogues as new acetylcholinesterase (AChE) inhibitors

The present work proposed the preparation of triazolic analogues of tyrosol, a biophenol found in olive oil and whose wide range of bioactivities has been the target of many studies. We obtained fifteen novel tyrosol derivatives and the compounds of the series were later evaluated as acetylcholinesterase (AChE) inhibitors. The study of AChE inhibition is important for the development of new drugs and pesticides, and especially the research for managing Alzheimer's disease. The most active compound, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (30), showed IC₅₀ value of 14.66 ± 2.29 μmol L⁻¹. Docking experiments corroborated by kinetic assay are suggestive of a competitive inhibition mechanism. Derivatives interacted with amino acids from the AChE active site associated to the development of Alzheimer's disease. The results indicate that the compounds synthesized have a high potential as prototypes for the development of new acetylcholinesterase inhibitors.     

Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA

A series of 2-phenyl-benzopyranopyrimidine (PBPP) derivatives with alkylamino side chains were synthesized and found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time. Their interactions with telomeric G-quadruplex DNA were studied with FRET melting, surface plasmon resonance, CD spectroscopy, and molecular modeling. Our results showed that the disubstituted PBPP derivatives could strongly bind to and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. In comparison, the mono substituted derivatives had much less effect on the G-quadruplex, suggesting that the disubstitution of PBPP is essential for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the PBPP derivatives and their cellular effects were studied, and compound 11b was found to be the most promising compound as a telomerase inhibitor and telomeric G-quadruplex binding ligand for further development for cancer treatment.     

含三唑结构的新型稠合三环2(5H)-呋喃酮衍生物的合成

利用系列含烯二炔结构的2(5H)-呋喃酮衍生物与叠氮化钠发生串联的成环反应, 在优化的反应条件下, 即反应溶剂为DMF、反应时间48 h、反应温度30 ℃时、NaN₃为1.5 equiv., 以中等产率(42%～62%)合成了系列新型的稠合三环2(5H)-呋喃酮衍生物, 其可以进一步高产率地(94%～96%)衍生为吡啶稠合的2(5H)-呋喃酮化合物. 所有新化合物的结构用IR, ¹H NMR, ¹³C NMR, MS, 元素分析等方法进行了表征. 该串联反应合成途径简捷、反应条件温和, 无需添加催化剂, 可为具有含三唑结构的稠杂环化合物合成提供简便的途径.     

Synthesis of novel apio carbocyclic nucleoside analogues as selective a(3) adenosine receptor agonists

On the basis of the biological activity of neplanocin A and apio-dideoxyadenosine (apio-ddA), novel apio-neplanocin A analogues 5a-d, combining the properties of two nucleosides, were stereoselectively synthesized. The apio moiety of the target nucleosides 5a-d was stereoselectively introduced by treating lactol 10 with 37% formaldehyde in the presence of potassium carbonate. The carbasugar moiety of neplanocin A was successively built by exposing diene 12 on a Grubbs catalyst in methylene chloride. The final nucleosides 5a-d were synthesized from the condensation of the glycosyl donor 14 with nucleic bases under the standard Mitsunobu conditions. Similarly, apio-aristeromycin 6 and (N)-apio-methanocarbaadenosine 7 were derived from the common intermediate 13 using catalytic hydrogenation and Simmons-Smith cyclopropanation as key steps. All of the final nucleosides 5a-d, 6, and 7 did not show significant inhibitory activity against S-adenosylhomocysteine hydrolase (SAH) up to 100 muM, maybe due to the absence of the secondary hydroxyl group at the C3'-position, which should be oxidized by cofactor-bound NAD(+). However, apio-neplanocin A (5a) showed potent and highly selective binding affinity (K(i) = 628 +/- 69 nM) at the A(3) adenosine receptor without any binding affinity at the A(1) and A(2A) adenosine receptors. In conclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugars using stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A(3) adenosine receptor agonist, which play a great role in developing new A(3) adenosine receptor agonist as well as in identifying the binding site of the receptor.     

An oxacalix[2]arene[2]pyrimidine-bis(Zn-porphyrin) tweezer as a selective receptor towards fullerene C70

An oxacalix[2]arene[2]pyrimidine-bis(Zn^II-porphyrin) conjugate was readily prepared via nucleophilic aromatic substitution of a phenolic AB₃-Zn-porphyrin on the upper rim of a (1,3-alternate) 5,17-bis(methylsulfonyl)oxacalix[4]arene precursor. Efficient 1:1 complex formation between the ‘jaws’ bisporphyrin tweezer and fullerene C₇₀ was evidenced by ¹H NMR titrations (K = 3.0 × 10⁴ M⁻¹), while no detectable complexation could be observed with C₆₀. On the other hand, an analogous oxacalix[4]arene-bis(Cu-corrole) conjugate did not show any measurable (C₆₀ or C₇₀) fullerene binding.     

Synthesis,Structure and Biological Activities of 2-(1H- 1,2,3-Benzotriazol-1-yl)-1-(4-methylphenyl)-2- (1H-1,2,4-triazol-1-yl)-1-ethanone

IntroductionTriazole derivatives have become the most rapidlyexpanding group of antifungal compounds with advanta-ges of lowtoxicity, high oral bioavailability and broad-spectrum antifungal activity, which can be used againstfungi including most yeasts an…     

Syntheses, Structure and Biological Activities of 2-（ 1H-Benzo [ 1,2,3 ] triazole-l-yl） -1-（3-methyl-4-bromobiphenyl） - 2- （ 1H-1, 2,4-triazole-1 -yl ） ethanone

Introduction 1,2,4-Triazole derivatives represent an interesting class of heterocyclic compounds[1] and have become the most rapidly expanding group of antifungal compoundswith the advantages of toxicity, high oral bioavailability, and broad spectrum of activity against several fungi, including most yeasts and folanentous fungi[2-4].     

Preparation of 4,5 disubstituted-2H-1,2,3-triazoles from (Z)-2,3-diaryl substituted acrylonitriles

2H-1,2,3-Triazoles (2) were synthesized by [3+2] cycloaddition of (Z)-2,3-diaryl substituted acrylonitriles (1) with sodium azide and ammonium chloride in DMF/water. This method represents a facile and efficient reaction procedure for the synthesis of 4,5-diaryl-2H-1,2,3-triazoles in modest to good yields.     

Fixed-charge labels for simplified reaction analysis: 5-hydroxy-1,2,3-triazoles as byproducts of a copper(I)-catalyzed click reaction

High-resolution multistage mass spectrometric studies of isotope-labelled derivatives of a fixed-charge labelled sugar triazole assisted the identification of 5-hydroxy-1,2,3-triazoles as byproducts of the copper(I)-catalyzed cycloaddition of azides and terminal alkynes. Reaction optimization with inclusion of the auxiliary ligand, tris(benzyltriazolylmethyl)amine furnished an improved ligation protocol in which formation of the 5-hydroxytriazole is mitigated.     

Cu(II) complex of an abiotic receptor as highly selective fluorescent sensor for acetate

A copper complex having quinoline moiety as fluorophore has been synthesized. The anion recognition behavior of the receptor and its copper complex has been studied in acetonitrile and in acetonitrile: H₂O (95:5 v/v). The copper complex shows high selectivity toward acetate over other anions studied such as F⁻, Cl⁻, Br⁻, I⁻, OAc⁻, dl-malate, l-mandelate, benzoate, isophthalate, , and .     

Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists

A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor although it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.     

Carborane-based metal-organic frameworks as highly selective sorbents for CO(2) over methane

Separation of CO(2)/CH(4) mixtures was studied in carborane-based metal-organic framework materials with and without coordinatively unsaturated metal sites; high selectivities for CO(2) over CH(4) ( approximately 17) are obtained, especially in the material with open metal sites.     

2-Pyridylaldehydebenzoylhydrazone derivatives as highly selective precolumn chelating reagents for nickel (II) ion in kinetic differentiation mode high-performance liquid chromatography

2-Pyridylaldehydearoylhydrazones have been examined as reagents for precolumn derivatization of metal ions in the HPLC-spectrophotometry system. With the simplest analog, 2-pyridylaldehydebenzoylhydrazone (PAB), among 11 metal ions only Ni(II) ion gives the peak while the other metal chelates seem to be dissociated on an HPLC column where no added PAB is present in the eluent solutions. All other PAB analogs exhibit the peak for Ni(II) ion as well as Co(III) ion. In one reagent system, V(V) and Fe(II) chelates also appear in the chromatograms. It has been stressed that the selectivity principle is the kinetic differentiation (KD) towards metal chelates associated with the HPLC processes. The specificity for Ni(II) ion is in close relation to a key structure of the ligand molecules which provides an N,N,O coplanar coordination environment to form two five-membered chelate rings. An extremely selective and sensitive KD-HPLC method for the quantitation of Ni(II) ion at the ultra-trace levels was assessed; the detection limit (3 _Blank) for Ni(II) ion was down to 5.34 × 10^–9 mol l^–1 (31.5 pg in a 100 l injection) and the excellent applicability was checked using coal fly ash samples.     

Bis(indolyl)methane derivatives as highly selective colourimetric and ratiometric fluorescent molecular chemosensors for Cu cations

New probes based on bis(indolyl)methane derivatives only sense Cu²⁺ among other heavy and transition metal (HTM) ions through two different channels: the colourless to orange or purple colour change, that is visible to the naked eye, and a remarkable enhancement of the fluorescence along with a large red-shift in emission, in a water containing medium (CH₃CN/H₂O).