Synthesis,In Vitro Antimicrobial and Antioxidant Activities of Some New 4,5‐Dihydro‐1H‐1,2,4‐triazol‐5‐one Derivatives

A series of compounds derived from 4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐one were synthesized and characterized by spectral data. The 12 new compounds were analyzed for their potential in vitro antioxidant activities by three different methods. Compound 4f showed the best activity for the iron binding. In addition, the compounds 4 were titrated potentiometrically with tetrabutylammonium hydroxide in non‐aqueous solvents. The RP‐HPLC capacity factors (k′) of the series were also determined on a C18 column, with methanol/water as the mobile phase. The correlation between log k′ with the percentage of methanol in the mobile phase was used for the determination of the log k_w values for these compounds. The antimicrobial activities of these compounds were also screened against bacteria and yeast.     

2‐Pyridinyl‐4(3H)‐Quinazolinone: A Scaffold for Anti‐influenza A Virus Compounds

A series of 2‐pyridinyl‐3‐substituted‐4(3H)‐quinazolinones were synthesized, and their anti‐influenza A virus activities were determined using the cytopathic effect inhibition assay. Most of the compounds were potent with IC₅₀ values ranging from 51.6 to 93.0 μm , which are better than that of the currently marketed drug ribavirin. The molecular mechanisms of the new compounds were investigated using neuraminidase inhibition assay, cellular NF‐κB signaling pathway inhibition assay, and computational docking. Compound 4e , which is a N3 imidazol‐1‐ylpropyl‐substituted derivative of 2‐pyridinyl‐4(3H)‐quinazolinone, had the most potent anti‐influenza A virus activity in vitro, and inhibited both virus neuraminidase and cellular NF‐κB signaling pathway. In conclusion, 2‐pyridinyl‐4(3H)‐quinazolinone is a new scaffold for the design of potent anti‐influenza A virus compounds, offering an alternative approach to tackle influenza drug resistance.     

Inhibitory action of naphtho[1,2‐b]furan‐4,5‐dione on hepatocyte growth factor‐induced migration and invasion of MDA‐MB‐231 cells: Mechanisms of action

Naphtho[1,2‐b]furan‐4,5‐dione (NFD), a bioactive component of Avicennia marina, has been shown to exhibit anticancer activity. The aim of the present study was to explore the effect of NFD on hepatocyte growth factor (HGF)‐induced cell migration and invasion of MDA‐MB‐231 human breast cancer cells, as well as the underlying mechanism of action. Cell viability was determined using the 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide assay, western blot analysis was used to measure protein expression and cell migration and invasion were evaluated by the cell wound healing assay, Boyden chamber assay and gelatin zymography. When cells were treated with non‐toxic concentrations of NFD (1–3 μmol/L, 24 h), NFD concentration‐dependently inhibited HGF‐promoted cell migration and invasion. Simultaneously, NFD efficiently suppressed c‐Met phosphorylation and downstream activation of phosphatidylinositol 3‐kinase (PI3K) and Akt. In addition, NFD inhibited the phosphorylation of IκB kinases and IκBα and nuclear translocation of nuclear factor (NF)‐κB, as well as matrix metalloproteinase (MMP)‐9 activity. Furthermore, the c‐Met inhibitor PHA665752 (10 μmol/L) inhibited HGF‐induced MMP‐9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of c‐Met activation. In conclusion, the results of the present study suggest that NFD inhibits HGF‐induced invasion and migration of MDA‐MB‐231 cells via HGF‐ and/or c‐Met‐mediated PI3K/Akt and NF‐κB signalling pathways, leading to downregulation of MMP‐9 expression and cell migration.     

Synthesis,Evaluation of Pharmacological Activities and Quantitative Structure–Activity Relationship Studies of a Novel Group of bis(4‐Nitroaryl‐1,4‐dihyropyridine)

Voltage‐dependent calcium channels are crucial targets for a wide range of clinically active pharmacological agents. From these agents, 1,4‐dihydropyridines constitute a group of small organic compounds are based on a core pyridine structure which can both block and enhance calcium currents. They are considered specific for L‐Type calcium channels; however, other channel types, and in particular certain T‐Type channels, may show sensitivity to dihydropyridine compounds. In this study, we synthesized a novel group of bis‐1,4‐dihydropyridines using the procedure reported by Dagnino that involved the condensation of n‐alkyl diacetoacetate (n = 2–7) with methyl‐3‐aminocrotonate and nitrophenylaldehyde. The synthesis was run under two conditions: (i) reflux and (ii) microwave. Calcium channels antagonist activity were determined in vitro using guinea‐pig ileum longitudinal smooth muscle assay. Synthesis of these compounds was confirmed with 1H‐NMR, IR and mass spectrometry. Then IC₅₀ of them are calculated and compared with Nifedipine. Finally, the result of this pharmacological assay was used in quantitative structure–activity relationship studies utilizing multiple linear regression analysis. Most of these compounds are less active compared with Nifedipine. Decrease in activity is the result of increase in steric hindrance. The quantitative structure–activity relationship study indicates that the activity is related to the electrostatic and topological parameters and the distance between two C5‐esteric groups of 1,4‐dihydropyridine rings.     

1,3,5,8‐Tetrahydroxy‐9H‐xanthen‐9‐one exerts its antiageing effect through the regulation of stress‐response genes and the MAPK signaling pathway

The antioxidative effects of 30 xanthone derivatives (XDs) ( XD‐ n , n = 1–30) in HepG2 cells were evaluated by the cellular antioxidant activity assay. Results showed that all XDs were antioxidants and 1,3,5,8‐tetrahydroxy‐9H‐xanthen‐9‐one ( XD‐2 ) was the most active antioxidant. The all‐oxygenated substituted xanthones extended the lifespan of wild‐type N2 nematodes under normal culture conditions and XD‐2 was the best one. XD‐2 eliminated excessive intracellular reactive oxygen species and enhanced the expression levels and activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. XD‐2 inhibited the H₂O₂‐increased phosphorylation levels of c‐JUN N‐terminal kinase, extracellular signal‐regulated kinase, and p38 in HepG2 cells. In vivo, XD‐2 also extended the lifespan of wild‐type N2 nematodes under oxidative stress induced by paraquat, but failed in extending the lifespan of CF1038 (daf‐16 deletion) and AY102 (pmk‐1 deletion) mutant nematodes. It was revealed by real‐time polymerase chain reaction that the genes daf‐16, sir‐2.1, akt‐1, and age‐1 were all inhibited by paraquat stimuli, while XD‐2 reversed these inhibitions; in contrast, paraquat stimuli upregulated both the skn‐1 and pmk‐1 genes. However, treatment by  XD‐2 further increased the levels of both genes. These pieces of evidence implied that XD‐2 promotes longevity through endogenous signaling pathways rather than through the antioxidative activity alone. Taken all together, it may be concluded that XD‐2 is a promising antiageing agent.     

Synthesis and in‐vitro Antimycobacterial Evaluation of 1‐(Cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐ 8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids

Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC²). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM.     

Synthesis and screening of substituted 1,4‐naphthoquinones (NPQs) as antifilarial agents

Eleven amino‐substituted 1,4‐naphthoquinones were synthesized via the reaction of 1,4‐naphthoquinone with different primary and secondary mono‐ and diamines in the presence of dichloromethane ethanol (1:2) solvent at room temperature. All compounds were purified by flash column chromatography, characterized by TLC, HPLC, ¹³C‐NMR, ¹H‐NMR, and FT‐IR spectral analysis and were evaluated in vitro for antifilarial activity using adult bovine filarial worm Setaria digitata by assessing worm motility and MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) reduction. Seven of the 11 compounds had macrofilaricidal activity with compounds 9 (2‐[(1,3‐dimethylbutyl) amino] naphthalene‐1,4‐dione) and 11 (2‐(4‐methylpiperazin‐1‐yl) naphthalene‐1,4‐dione) having maximum activity (ED₅₀ values of 0.91 and 1.2 µM, respectively, at 48 h). The effect of different substitutions on antifilarial activity is discussed. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

13C‐ and 14C‐labelling of N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐methyleneamino] guanidinium acetate

N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐¹³C₄‐methyleneamino]guanidinium acetate has been synthesized by a four‐step procedure. This involved reduction of the Weinreb amide N,N′‐dimethyl‐N,N′‐dimethyloxybutane‐1,4‐diamide‐1,2,3,4‐¹³C₄ by Dibal‐H to give the corresponding unstable dialdehyde which is reacted in situ with 4‐chloroaniline to form 1‐(4‐chlorophenyl)‐1H‐pyrrole‐¹³C₄. This pyrrole analogue underwent a Vilsmeyer acylation with POCl₃/DMF followed by final reaction with aminoguanidine bicarbonate to produce the desired labelled compound with 99% atom ¹³C. By using DMF [α‐¹⁴C] a radio‐labelled analogue was synthesized with a specific activity of 60 mCi/mmol. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and Biological Activity of Some 1,3‐Dihydro‐2H‐3‐benzazepin‐2‐ones with a Piperazine Moiety as Bradycardic Agents

A series of 1,3‐dihydro‐2H‐3‐benzazepin‐2‐ones with a piperazine moiety were designed and synthesized by treating the common intermediate of 1,3‐dihydro‐7,8‐dimethoxy‐3‐[3‐(1‐piperazinyl)propyl]‐2H‐3‐benzazepin‐2‐ones with a variety of N‐aryl‐2‐chloroacetamides and acyl chlorides. Their structures have been characterized by ¹H‐NMR, MS, and elemental analysis. The title compounds were evaluated for their bradycardic activity in vitro. Most of the synthesized compounds exhibited some vasorelaxant activity and heart‐rate‐reducing activity with bradycardic potency.     

Synthesis and in‐vitro Cytotoxic Evaluation of Novel Pyridazin‐4‐one Derivatives

A new series of N‐aryl‐4‐oxo‐1,4‐dihydro‐pyridazine‐3‐carboxylic acids has been synthesized by condensation of aryldiazonium with 4‐hydroxy‐6‐methyl‐2‐pyrone. Some of these compounds exhibited in‐vitro cytotoxic activity with moderate to excellent growth inhibition against the murine P815 mastocytoma cell line. Compound 5b showed an important cytotoxic activity against cell line P815 (IC₅₀ = 0.40 μg/mL).