Synthesis and molluscicidal activity of new cinnoline and pyrano [2,3-c]pyrazole derivatives

2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.     

Ecofriendly synthesis of pyrano[2,3-d]pyrimidine derivatives and related heterocycles with anti-inflammatory activities

A versatile, efficient, clean, and facile method was used for the synthesis of pyrano[2,3-d]pyrimidine derivatives by the one-pot three-component condensation reaction of thiobarbituric acid and malononitrile with p-chlorobenzaldehyde, using Fe₃O₄ or ZnO or Mn₃O₄ as nanostructure catalysts. The catalyst could be easily recovered using an external magnet and reused for six cycles with almost a consistent activity. A series of polyheterocyclic compounds containing five and/or six rings fused with each other was designed. The anti-inflammatory activities for some of the newly synthesized compounds were evaluated. All the synthesized compounds were characterized on the basis of their elemental analyses and spectral data.     

Synthesis and antimicrobial evaluation of naphtho[2,1-b]pyrano[2,3-d]pyrimidine and pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

Several novel naphtho[2,1-b]pyrano[2,3-d]pyrimidines, pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines and their coumarin-3-yl derivatives were synthesized. Some of these derivatives exhibited pronounced antimicrobial activities.     

Synthesis and molluscicidal activity of some 1,3,4-triaryl-5-chloropyrazole, pyrano[2,3-c]pyrazole, pyrazolylphthalazine and pyrano[2,3-d]thiazole derivatives

2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of malononitrile 2a-d to afford the triaryl-5-chloropyrazoles 3a-d, respectively. 1a reacts with the active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and 14a, b--depending on the substitution in the pyrazole ring. Compound 1a reacts also with the pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a-c to afford the pyrano[2,3-d]thiazoles 20a-c, respectively. It reacts also with the malononitrile dimer 21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively. The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.     

A novel synthesis and molluscicidal activity of some functionally substituted pyridine, pyrido[3,2-c]pyridazine, and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives

Ethyl benzoylacetate reacts with the malononitrile dimer to afford 4-amino-5-benzoyl-2-dicyano methyl-6-hydroxypyridine, which undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives. These azo derivatives could be cyclized into pyrido[3,2-c]pyridazine and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives upon reflux in ethanolic NaOH, presumably via their hydrazo tautomers. The molluscicidal activity of these compounds was evaluated.     

Nitriles in Heterocyclic Synthesis: Synthesis of New Pyrazolo [1,5-a]pyrimidines,Pyrano[2,3-c]pyrazoles and Pyrano[3,4-c] pyrazoles

New pyrazolo[1,5-a]pyrimidines, pyrano[2,3-c]pyrazoles and pyrano[3,4-c]pyrazoles were synthesised by reaction of the α,β-unsaturated nitriles 1, 13 and 16 with 3-amino-2-pyrazolin-5-one (2) , 1-phenylpyrazolidine-3,5-dione (5) , and 5-amino-3-phenylpyrazole (10) .     

Synthesis of pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine derivatives for antiviral evaluation

6-Amino-3-methyl-4-(4-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) was used as a precursor for preparation of some novel 3,7-dimethyl-4-(4-nitrophenyl)-2,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine derivatives 3-6, and some of their corresponding N(2)- and C(5)-S-acyclic nucleosides 7 and 8. Furthermore, the preparation of 5-amino-1-[3,7-dimethyl-4-(4-nitrophenyl)-2,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5-yl]-1H-pyrazole derivatives 10-16 were described. Some of the prepared products were selected and tested for antiviral activity against Herpes Simplex Virus type-1 (HSV-1).     

Multicomponent synthesis of poly-substituted benzo[a]pyrano[2,3-c]phenazine derivatives under microwave heating

A new one-pot two-step tandem synthesis of highly functionalized benzo[a]pyrano[2,3-c]phenazine derivatives via microwave-assisted multicomponent reactions of 2-hydroxynaphthalene-1,4-dione, diamines, aldehydes, and malononitrile is reported. The procedures are facile, avoiding time-consuming and costly syntheses, tedious workup, and purifications of precursors, as well as protection/deprotection of functional groups. The method is expected to find application in the combinatorial synthesis of biologically active compounds, since phenazine and chromene motifs have a broad spectrum of biological activities.     

Three-component synthesis of pyrano[2,3-d]-pyrimidine dione derivatives facilitated by sulfonic acid nanoporous silica (SBA-Pr-SO3H) and their docking and urease inhibitory activity

Background

A straightforward and efficient method for the synthesis of pyrano[2,3-d]pyrimidine diones derivatives from the reaction of barbituric acid, malononitrile and various aromatic aldehydes using SBA-Pr-SO₃H as a nanocatalyst is reported.

Results

Reactions proceed with high efficiency under solvent free conditions. Urease inhibitory activity of pyrano[2,3-d]pyrimidine diones derivatives were tested against Jack bean urease using phenol red method. Three compounds of 4a, 4d and 4l were not active in urease inhibition test, but compound 4a displayed slight urease activation properties. Compounds 4b, 4k, 4f, 4e, 4j, 4g and 4c with hydrophobic substitutes on phenyl ring, showed good inhibitory activity (19.45-279.14 μM).

Discussion

The compounds with electron donating group and higher hydrophobic interaction with active site of enzyme prevents hydrolysis of substrate. Electron withdrawing groups such as nitro at different position and meta-methoxy reduced urease inhibitory activity. Substitution of both hydrogen of barbituric acid with methyl group will convert inhibitor to activator.     

Activated Nitriles in Heterocyclic Synthesis: Novel Syntheses of Pyrano[2,3-b]pyridines and Pyrano[2,3-d]pyrimidines

Reactions of β-(2-furanyl)- and β-(2-thienyl)-acrylonitrile with ethyl acetoacetate are reported. They lead to new polyfunctional derivatives of pyrano[2,3-b]pyridine and pyrano[2,3-d]-pyrimidine. The structures of these products and the mechanisms of their formation are reported.     

Synthesis and anticonvulsant activity of pyrano[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d] pyrimidine derivatives and pyrimido[5′,4′:2,3]-thieno[2,3-c]isoquinoline derivatives

Methods for the synthesis of condensed thieno[3,2-d]pyrimidines based on pyrano[4,3-d]thieno[2,3-b]pyridines and thieno[2,3-b]isoquinolines have been developed and a series of new derivatives have been synthesized. The anticonvulsant activity of the synthesized compounds has been studied. Several compounds possessing specific anticonvulsant activity with respect to corazole-induced convulsions are revealed. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 9, pp. 14–16, September, 2007.     

Potent anticonflict activity and lessening of memory impairment with a series of novel [1]benzothieno[2,3-c]pyridines and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines

[1]Benzothieno[2,3-c]pyridines (10a-c, 11, 12a-t, and 13a,b) and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines (3a-c, 7, 8a-c, and 9) were synthesized. The compounds are bioisosteres of beta-carbolines and 1,2,3,4-tetrahydro-beta-carbolines where the indole nitrogen is replaced by sulfur. Their pharmacological activity was evaluated in a water lick conflict test in rats and a passive avoidance test in mice. In the 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine series, the presence of ethyl ester (3b) or cyclohexyl carboxamide (7) groups at C-3 conferred good anticonflict activity and lessening of memory impairment, while N-acylation of 3b abolished activity. In the [1]benzothieno(2,3-c]pyridine series, the aminoethyl carboxamide (12a) group at C-3 also conferred activity, but other amides studied were not active. The most potent compounds (3b, 7, and 12a) were also administered orally and had potent anticonflict and antiscopolamine amnesia-reversal activity. These compounds did not bind to the BZP receptor in spite of having structures similar to those of beta-carbolines. Compound 7 bound strongly to 5-HT1A receptors and would be expected to be a novel anxiolytic.     

Synthesis and pharmacological properties of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines

A series of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines was synthesized starting from the corresponding bicyclic 1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (CFMs), previously described as noncompetitive AMPA-type glutamate receptor antagonists, more potent than GYKI 52466. New synthesized compounds proved to be able to protect against seizures induced by means of auditory stimulation in DBA/2 mice and compound 8f the most active of the series showed anticonvulsant properties comparable to GYKI 52466.     

Further modifications of 1H-pyrrolo[2,3-b]pyridine derivatives as inhibitors of human neutrophil elastase

Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes and is considered to be a multifunctional enzyme. HNE is also involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrrolo[2,3-b]pyridine derivatives of our previously reported potent HNE inhibitors. Our results show that position 2 of the pyrrolo[2,3-b]pyridine scaffold must be unsubstituted, and modifications of this position resulted in loss of HNE inhibitory activity. Conversely, the introduction of certain substituents at position 5 was tolerated, with retention of HNE inhibitory activity (IC₅₀ = 15–51 nM) after most substitutions, indicating that bulky and/or lipophilic substituents at position 5 probably interact with the large pocket of the enzyme site and allow Michaelis complex formation. The possibility of Michaelis complex formation between Ser195 and the ligand carbonyl group was assessed by molecular docking, and it was found that highly active HNE inhibitors are characterized by geometries favorable for Michaelis complex formation and by relatively short lengths of the proton transfer channel via the catalytic triad.     

Reaktionen mit 4-Hydroxy-5-oximino-7-methyl-5H-pyrano[2,3-b]pyridin-8-oxid

Reactions with 4-Hydroxy-5-oximino-7-methyl-5H-pyrano[2,3-b]pyridine 8-Oxide The pyrano[2,3-b]pyridine 1a with a vinylogous hydroxamic acid structure reacts with dimethyl sulphate, acetic anhydride or nitric acid to give the monomethyl ether 2 , the diacetyl compound 3 or the mono- and dinitro derivatives 5 and 6 . Reduction reactions leading to 4-hydroxy-5-oximinopyrano[2,3-b]pyridine 4 or the 4-hydroxy-2-pyridone derivative 8 are also described.     

四氢吡咯里嗪并[2,1-c]喹啉衍生物的合成及其镇痛作用考察

目的研究5,6,6a,11b-四氢-7H-吡咯里嗪并[2,1-c]喹啉类化合物的镇痛作用构效关系,寻找具有镇痛活性的新型四氢喹啉类化合物。方法以吡里酮为原料,合成系列化合物。用乙酸致小鼠扭体法测定该类化合物的镇痛活性。结果合成了13个目标化合物,经波谱分析确证其结构。镇痛活性试验表明,所合成的部分化合物具有较明显的镇痛作用。结论该类化合物值得进一步研究。     

4-Hydroxycoumarin in heterocyclic synthesis. Part III. Synthesis of some new pyrano[2,3-d]pyrimidine, 2-substitute

The synthesis of new [1]benzopyrano[3',4':5,6]pyrano[2,3-d]pyrimidines and related heterocycles has been reported. The key intermediate 2-amino-3-cyano-4-methyl-4H,5H-pyrano[3,2-c][1]benzopyran-5-one (3) was obtained in one pot synthesis from the reaction of 4-hydroxycoumarin and acetaldehyde-malononitrile (2). The antimicrobial screening was performed for some of the synthesized compounds.     

Isoindolo[2,1-c][2,3]benzodiazepine

Isoindolo[2,1-c][2,3]benzodiazepines Reaction of the isocoumarin 2 with methylhydrazine yields the spiro-compound 3b as the major product. Compound 3b was converted to the title compounds 8 and 9 .     

Synthesis and molluscicidal activity of new chromene and pyrano[2,3-c]pyrazole derivatives

The chromene derivative 4 reacts with acetic anhydride, phenylisothiocyanate and ethyl orthoformate to afford the N-acetyl derivative 6, the chromenopyrimidine 8 and the formimidate 9, respectively. 2-(1H-Indol-3-ylmethylene)-malononitrile 10b reacts with 1,3-cyclohexanedione and dimedone 11a, b to afford the 4(3-indolyl)-chromene derivatives 12a, b respectively, and with the pyrazolone derivatives 13a-d to afford the arylidene exchange derivatives 14a-c and the pyranopyrazole derivative 15, respectively. The arylidene derivatives 10a, b react also with indane-1,3-dione 16 to afford the arylidene exchange derivatives 18a, b. The molluscicidal activity of the synthesized compounds towards Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni, was investigated and most of them showed weak to moderate activity.     

Synthesis and antimicrobial evaluation of new pyrano[4,3-b]pyran and Pyrano[3,2-c]chromene derivatives bearing a 2-thiophenoxyquinoline nucleus

A new series of pyrano[4,3-b]pyran 4a-i and pyrano[3,2-c]chromene 6a-r derivatives bearing a 2-thiophenoxyquinoline nucleus were synthesized by reaction of 2-(4-(un)-substituted thiophenoxy)quinoline-3-carbaldehydes 2a-i with 6-methyl-4-hydroxypyran-2-one 3 and 4-hydroxy-6-(un)-substituted-2H-chromen-2-one 5a-b respectively and malononitrile at room temperature in the presence of KOH as a basic catalyst. All the compounds were screened against three Gram-positive bacteria (Streptococcus pneumoniae, Bacillus subtilis, Clostridium tetani), three Gram-negative bacteria (Salmonella typhi, Escherichia coli, Vibrio cholerae) and two fungi (Candida albicans, Aspergillus fumigatus) using the broth microdilution MIC (minimum inhibitory concentration) method. Upon antimicrobial screening, it was observed that the majority of the compounds were found to be active against Bacillus subtilis, Clostridium tetani and Candida albicans as compared to standard drugs.