Dione Derivatives Research Articles

Modified salicylanilide and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives as novel inhibitors of osteoclast differentiation and bone resorption.

Inhibition of osteoclast formation is a potential strategy to prevent inflammatory bone resorption and to treat bone diseases. In the present work, the purpose was to discover modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives as potential antiosteoclastogenic agents. Their inhibitory effects on RANKL-induced osteoclastogenesis from RAW264.7 cells were evaluated by TRAP stain assay. The most potent compounds, 1d and 5d, suppressed RANKL-induced osteoclast formation and TRAP activity dose-dependently. The cytotoxicity assay on RAW264.7 cells suggested that the inhibition of osteoclastic bone resorption by these compounds did not result from their cytotoxicity. Moreover, both compounds downregulated RANKL-induced NF-κB and NFATc1 in the nucleus, suppressed the expression of osteoclastogenesis-related marker genes during osteoclastogenesis, and prevented osteoclastic bone resorption but did not impair osteoblast differentiation in MC3T3-E1. Therefore, these modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones could be potential lead compounds for the development of a new class of antiresorptive agents.

Highly regio- and diastereoselective three-component reaction of acyclic/cyclic donor–acceptor carbenoids for the synthesis of angularly fused furocoumarins and spirooxindolylfurocoumarins

A highly regio- and stereoselective method has been developed for the synthesis of spiro[furo[3,4-c]chromene-1,3′-indoline]-2′,4(9bH)-dione derivatives via a three component reaction of cyclic diazoamide and aldehyde with methyl 2-oxo-2H-chromene-3-carboxylate, 3-acetyl-2H-chromen-2-one and 3-benzoyl-2H-chromen-2-one using 3 mol % of Rh2(OAc)4. Similarly, acyclic diazoesters also undergo smooth coupling with carbonyl compounds and 3-substituted coumarin in the presence of 1 mol % of Rh2(OAc)4 to afford a novel series of tetrahydro-1H-furo[3,4-c]chromene-1-carboxylates in 78–88% yield with high regio- and stereo-selectivity for the first time.

L-Proline-Catalysed Unusual Product Formation from the Reaction of 4- Hydroxydithiocoumarin and Aldehydes through a Pseudo-Three-Component Reaction

A convenient and highly efficient synthetic protocol is reported for the synthesis of hitherto unreported thiopyrano{2,3- b :6,5- b ′}bis(thiochromene)-12,14(13 H )-diones by a domino pseudo-three-component reaction utilizing 4-hydroxydithiocoumarin and aldehydes. Single-crystal X-ray crystallographic analysis of the 13-phenyl-12 H -thiopyrano[2,3- b :6,5- b ′]bis(thiochromene)-12,14(13 H )- dione derivative shows a layered structure that is stabilized by the unexpected C–S···π interactions.

ChemInform Abstract: Synthesis, Structure, and Properties of New Spirooxindolodibenzodiazepine Derivatives.

An acid-catalyzed reaction of 3-(2-aminophenylamino)-5,5-dimethylcyclohexen-1-one with isatines leads to the formation of the earlier undescribed 3,3-dimethyl-2,3,4,5,10,11-hexahydrospiro[1H-dibenzo[b,e][1,4]diazepine-11,3′-2H-indole]-1,2′-dione derivatives (6). Spiranes 6 upon heating undergo auto-redox rearrangement with disintegration to 3,3-dimethyl-1,2,3,4-tetrahydrophenazine and the corresponding oxindole. Crystals of four derivatives of compound 6 were studied by X-ray diffraction method.

ChemInform Abstract: A Novel, Chemoselective One‐Pot Procedure for the Preparation of 3H‐Spiro[isobenzofuran‐1,2′‐pyrrole]‐3,3′(1′H)‐dione Derivatives via Oxidative Cleavage of 3a,8b‐Dihydroxyindeno[1,2‐b]pyrroles.

A one-pot, efficient and chemoselective procedure for the synthesis of new 3H-spiro[isobenzofuran-1,2′-pyrrole]-3,3′(1′H)-dione derivatives has been developed which involves room temperature oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles themselves synthesized from the reaction of ninhydrin and enaminones in 30% ethanol. A reasonable mechanism is proposed for the oxidation reaction based on the results of this study and our previous related work.

Reaction of 1-(4-methylphenyl)-5-phenyl-2,3-dihydro-1H-pyrrole-2,3-dione with tris(diethylamino)phosphine. A new synthesis of 3,3′-bipyrrolylidene-2,2′-dione derivatives

Heterocyclic α-diketones are used as starting materials for the synthesis of new heterocyclic compounds possessing useful properties, from those exhibiting specific biological activity to new functional materials [1–3]. A particular place is occupied by pyrrole-2,3dione and 3,3′-bipyrrolylidene derivatives which have recently found increasing application in the preparation of synthetic analogs of natural chromophore systems [4], as well as in organic semiconducting and photovoltaic devices [5].

The Convenient Synthesis of 11‐Methyl‐3,8‐disubstituted‐12‐aryl‐3,4,7,8,9,12‐hexahydro‐1H‐chromeno[2,3‐b]quinoline‐1,10(2H)‐dione Derivatives

The 2‐arylidene‐3‐oxobutanenitrile derivatives 2 were prepared by the Knoevenagel condensation between aldehydes and 3‐oxobutanenitrile 1, which was obtained by acid hydrolysis of β‐aminocrotononitrile. 3‐Acetyl‐2‐amino‐4H‐chromen‐5(6H)‐one derivatives 3 were synthesized by reaction of 2‐arylidene‐3‐oxobutanenitrile 2 and 5‐substituted‐1,3‐cyclohexanedione in ethylene glycol. The 11‐methyl‐3,8‐disubstituted‐12‐aryl‐3,4,7,8,9,12‐hexahydro‐1H‐chromeno[2,3‐b]quinoline‐1,10(2H)‐dione derivatives 4 were obtained by Friedländer reaction of compounds 3 with 5‐substituted‐1,3‐cyclohexanedione, using p‐toluenesulfonic acid monohydrate as catalyst. The structures of all novel compounds were characterized by elemental analysis, IR, MS, and 1H NMR spectra. The crystal and molecular structure of compound 4f has been determined by single crystal XRD analysis.

ChemInform Abstract: Design, Synthesis, and Antibacterial Evaluation of Some Novel 3′‐(Phenylamino)‐1′H‐spiro[indoline‐3,2′‐quinazoline]‐2,4′(3′H)‐dione Derivatives.

AbstractA variety of new spiro(indoline‐quinazoline) derivatives (IV) (13 examples) are synthesized via an efficient one‐pot, three‐component reaction of isatins, isatoic anhydrides, and phenylhydrazine using alum as a nontoxic, easily available catalyst.

Electrochemical formation of an ultrathin electroactive film from 1,10-phenanthroline on a glassy carbon electrode in acidic electrolyte.

The electrochemical reduction of 1,10-phenanthroline in aqueous acidic electrolyte at a glassy carbon electrode led to the covalent modification of the electrode. Thereafter, the deposited film can be switched to an electroactive form by electrochemical oxidation. An electroactive film can be also generated by alternate reductive and oxidative voltammetric cycling in a 1,10-phenanthroline/aqueous sulfuric acid solution. First, the electrochemical procedure for the formation of a film is presented. Second, the morphology and chemical structure of 1,10-phenanthroline coatings were investigated by atomic force microscopy, time-of-flight secondary ion mass spectrometry, X-ray photoelectron spectroscopy, and electrochemical techniques. The ultrathin (<15 nm) electrodeposited films consist of oligomeric species. The coatings deposited in alternate and/or continuous reductive and oxidative steps contain oxygen atoms incorporated into the oligomer backbone. The preliminary results point out the formation of a dione derivative that is responsible for the electroactivity of the grafted layer.

Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity

Nucleos(t)ide analog drugs profoundly suppress Hepatitis B virus (HBV) replication but rarely cure the infection, so therapy is usually life-long. The nucleos(t)ide analogs inhibit the viral DNA polymerase and often push HBV to the brink of extinction, so it may be possible to eradicate HBV by suppressing HBV replication further. The HBV ribonuclease H (RNaseH) is a logical new drug target because it is the second of only two viral enzymes essential for viral replication. We recently developed a low throughput screening pipeline for inhibitors of the HBV RNaseH and viral replication. Here, we screened a series of twenty-three nitrogen-based polyoxygenated heterocycles including sixteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives for anti-HBV RNaseH activity. Nine compounds inhibited the HBV RNaseH, but activity was marginal for eight of them. Compound #1 [2-hydroxyisoquinoline-1,3(2H,4H)-dione, HID] was the best hit with an IC50 of 28.1μM and an EC50 of 4.2μM. It preferentially suppressed accumulation of the viral plus-polarity DNA strand in replication inhibition assays, indicating that replication was blocked due to suppression of HBV RNaseH activity. It had a CC50 of 75μM, yielding a therapeutic index of ∼18. The EC50 value was 7-fold lower than the IC50, possibly due to cellular retention or metabolism of the compound, or higher affinity for the full-length enzyme than the recombinant form used for screening. These data indicate that the 2-hydroxyisoquinoline-1,3(2H,4H)-diones will have different structure–activity relationships for the HBV and HIV RNaseHs. Therefore, HID compounds may provide a foundation for development of more effective RNaseH inhibitors of HBV replication.

A Simple and Efficient Procedure for the One-pot Three-component Synthesis of Spiro[indoline-3,9′-tetrazolo[5,1-b]quinazoline]-2,8′(5′H)-dione in PEG–H2O Medium

Abstract Novel spiro[indoline-3,9′-tetrazolo[5,1-b]quinazoline]-2,8′(5′H)-dione derivatives have been synthesized by the three-component reaction of isatin, 5-amino-1H-tetrazole, and 5,5-dimethylcyclohexane-1,3-dione in PEG–H2O medium catalyzed by p-TSA. This protocol provides a simple one-step procedure with the advantages of easy work-up, mild reaction conditions, and environmental benignity.

A Facile Synthesis of Dispiro[indole-3,2′-Pyrrolidine-3,5″-[1,3]Thiazolane] Derivatives from 2,3,5-Trisubstituted-4-Thiazolidinones via 1,3-Dipolar Cycloaddition Reaction

A series of 2″,3″,4′-triaryl-1′-methyldispiro[indole-3,2′-pyrrolidine-3′,5″-[1,3]thiazolane]-2(1 H),4″-dione derivatives were successfully synthesised via a three-component 1,3-dipolar cycloaddition reaction of 2,3,5-trisubstituted-4-thiazolidinones, isatin and sarcosine in refluxing toluene. Such a strategy would provide access to a fast one-pot synthesis of spiroheterocycle in high yields.

Synthesis and DSC study a new pyridinedicarboximide diones derivatives, obtained under various conditions

The series of three 4-alkoxy-2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl]-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones were synthesized. The structures of all formed compounds were identified by elemental analysis, FTIR, and 1H NMR. The synthesized compounds were studied using differential scanning calorimetry and thermogravimetric analysis in order to determine the existence of multiple solid-state forms. Our measurements showed that the solvent, mechanical treatment, and quenching are the important factors. Two stable and one metastable modification were detected. Additionally, DFT calculations were performed.

A Catalyst‐Free Aqueous Synthesis of 2‐Amino‐7,9‐dihydrothieno[3′,2′:5,6]pyrido[2,3‐d]pyrimidine‐4,6(3H,5H)‐dione Derivatives

A series of novel 7,9‐dihydrothieno[3′,2′:5,6]pyrido[2,3‐d]pyrimidine‐4,6(3H,5H)‐dione derivatives were synthesized efficiently via the catalyst‐free reaction of aldehyde, ethyl 2,4‐dioxotetrahydrothiophene‐3‐carboxylate, and 2,6‐diaminopyrimidine‐4(3H)‐one through the sequence of deethoxycarbonylation and three‐component condensation in aqueous media. This protocol featured mild reaction conditions, high yields, easy work‐up, and environmentally friendly procedure.

Efficient synthesis of heterocyclic compounds derived from 2,6-dioxopiperazine derivatives and their evaluation for anti-inflammatory and anticancer activities

Piperazine dione derivatives (1a–j) on condensation with 2,6-pyridine dicarboxylic acid (2x), 3,5-pyridine dicarboxylic acid (2y) and 2,5-thiophene dicarboxylic acid (2z) gave corresponding heterocyclic compounds 3ax–3jz in excellent yields. All the newly synthesized compounds were fully characterized by spectroscopic means and elemental analysis. On screening for anti-inflammatory and for in vitro anticancer activity, compounds 3bx, 3cx, 3dx, and 3ex exhibited good anti-inflammatory activity, whereas compounds 3ay, 3az, 3cz, 3dx, 3ez, 3fx, 3gx, and 3hz exhibited good anticancer activity.

Highly active magnetically separable CuFe2O4 nanocatalyst: an efficient catalyst for the green synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H) dione derivatives

A facile and efficient procedure has been reported for the synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-diones by the condensation reaction of benzaldehydes, 1,3-cyclohexanediones and anilinolactones in the presence of CuFe2O4 as a reusable nanocatalyst with high catalytic activity in water. The notable advantages of this method are excellent isolated yields, short reaction times, simple workup procedure and little environmental impact. .

Microwave-assisted synthesis and myorelaxant activity of 9-indolyl-1,8-acridinedione derivatives

In this study a microwave-assisted method was applied for the synthesis of novel 9-(substituted indolyl)-3,4,6,7-tetrahydroacridine-1,8-(2H,5H,9H,10H)-dione derivatives. The structures of the compounds were confirmed by spectral methods including X-ray studies and elemental analysis.The Emax and pD2 values of the compounds and pinacidil were determined on noradrenaline precontracted tissues of isolated strips of rabbit gastric fundus smooth muscle. The obtained results indicated that some compounds and pinacidil produced concentration-dependent relaxation on the strips. The efficacy of compound 9 was higher than pinacidil.Docking studies were carried out to understand the interactions of the compounds with the active site of potassium channel. Methyl substituents on the acridine backbone and bromine atom on the indole ring led to more active compounds.

Synthesis of isoquinoline-1,3(2H,4H)-dione derivatives via cascade reactions of N-alkyl-N-methacryloyl benzamide with aryl aldehydes.

A cascade reaction between N-alkyl-N-methacryloylbenzamide and aryl aldehydes was developed to generate isoquinoline-1,3(2H,4H)-dione derivatives. The reaction involves oxidative cross-coupling of the activated alkene from the N-alkyl-N-methacryloylbenzamide with the aldehyde functional group (-CHO), followed by radical addition to the aromatic ring to afford isoquinoline-1,3(2H,4H)-dione derivatives in good yields under mild reaction conditions without either metal catalysts or organic solvents involved.

Oxidative Aromatization, Cytotoxic Activity Evaluation and Conformational Study of Novel 7-aryl-10, 11-dihydro-7H-chromeno [4, 3-b]quinoline-6, 8(9H, 12H)-dione Derivatives.

In the present work, novel 7-aryl-10, 11-dihydro-7H-chromeno [4, 3-b]quinoline-6, 8(9H, 12H)-dione derivatives were synthesized by oxidation of 7-aryl-8, 9, 10, 12-tetrahydro-7H-chromeno[4, 3-b]quinoline-6, 8-diones in the presence of silica sulfuric acid/NaNO2 with yields of 64-74%. Cytotoxic activity of synthesized compounds was assessed on three different human cancer cell lines (K562, LS180, and MCF-7). Synthesized compounds showed moderate cytotoxic activities. The most active one apeared to be 2e, containing a methoxy group on the meta position of phenyl ring (IC50 range in different cell lines: 11.1-55.7 µM). Furthermore; comparison of the cytotoxic activity of these novel oxidized derivatives with non-oxidized counterparts revealed that oxidation of dihydropyridine ring to pyridine, improves the activity especially in LS180 cell line. Conformational analysis revealed that some conformational aspects of oxidized derivatives such as orientation of C7-aryl substitute were clearly different from non-oxidized ones.

Amine functionalized MCM-41: an efficient heterogeneous recyclable catalyst for the synthesis of quinazoline-2,4(1H,3H)-diones from carbon dioxide and 2-aminobenzonitriles in water

Covalently linked amine functionalized MCM-41 was investigated as an efficient catalyst for the synthesis of various quinazoline-2,4(1H,3H)-dione derivatives from 2-aminobenzonitriles and carbon dioxide in water.