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.     

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

The synthesis of new naphtho[1',2':5,6]pyrano[2,3-d]pyrimidines and related heterocycles has been reported. The key intermediate 3-amino-8-bromo-1-(p-methoxyphenyl)-1H-naphtho[2,1-b] pyran-2-carbonitrile (3c) was obtained in one pot synthesis by treating alpha-cyanocinnamonitrile (1c) with 6-bromo-2-naphthol (2). Antimicrobial activity was shown for some of the synthesized compounds.     

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).     

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.     

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) .     

Structure-activity relationships and mechanism of action of antitumor benzo[b]pyrano[3,2-h]acridin-7-one acronycine analogues

The cytotoxic and antitumor activities of cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 3, 6-9 were strongly correlated with their ability to give covalent adducts with purified, as well as genomic, DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 in aqueous medium accounted for the intense activity of the cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 10-13. Compounds without acyloxy or hydroxy group at position 1, such as 15, 17, 18, and 22, were inert with respect to DNA and almost devoid of significant cytotoxic activity. Condensation of 5-amino-2,2-dimethyl-2H-chromene (26) with 3-bromo-2-naphthoic acid (27), followed by cyclization, gave access to 6-demethoxy analogues. Diacetate 32 and cyclic carbonate 33, both belonging to the latter series, were less reactive toward DNA and less cytotoxic than their 6-methoxy counterparts 3 and 34. DNA alkylation appears thus to play an important role in the antitumor properties of benzo[b]pyrano[3,2-h]acridin-7-one derivatives.     

Green approach towards the facile synthesis of dihydropyrano(c)chromene and pyrano[2,3-d]pyrimidine derivatives and their biological evaluation

A simple and efficient one-pot synthesis of heteroaryl-substituted dihydropyrano(c)chromenes and pyrano[2,3-d]pyrimidines has been developed. Reaction proceeds via initial Knoevenagel, subsequent Michael and final heterocyclization reactions of heteroaryl aldehyde, malononitrile, and barbituric acid/dimedone. Triethylammonium acetate acts as a green catalyst as well as reusable solvents for this reaction. Short reaction time, environment friendly procedure, reusability, and excellent yields are the main advantages of this procedure. All synthesized compounds have shown good antibacterial activity against different microbial stains but not active against cancer cell lines.     

Reactions with acetoacetanilide: Synthesis and antibacterial activity of some new pyran,pyrano[2,3-c]pyrazole and pyrano[2,3-c]-pyridine derivatives

The reaction of acetoacetanilide (1) with the α-cyanocinnamonitrile derivatives2 yielded the Michael adducts4 which could be converted into the pyrano[2,3-c] pyrazole derivatives5 via their reaction with hydrazine hydrate. Cyclisation of4 afforded the cyanoaminopyrans9 which could in turn be converted into the corresponding pyridine derivatives10. The pyranopyrazoles9 reacted with different activated nitrile derivatives (3a-c) to give the pyrano[2,3-c]pyridine derivatives13, 16 and19 respectively. The biological activity of the synthesised heterocyclic derivatives was investigated and discussed.     

Synthesis of thieno[2,3-d]pyrimidine derivatives and their antifungal activities

4-Chlorothieno[2,3-d]pyrimidines were prepared by the chlorination of 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidines with phosphoryl chloride. 4-Oxo-3,4,5,6,7,8-hexahydro[1]-benzo- and 4-oxo-6-phenylthieno[2,3-d]pyrimidine were synthesized by the cyclization of 2-acylaminothiophene-3-carboxamide derivatives with base. 2-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine was prepared by the treatment of 2-methyl-4-trichloromethylthieno-[2,3-d]pyrimidine with sodium hydroxide in aqueous methanol. A series of 4-alkylamino- and 4-arylaminothieno[2,3-d]pyrimidines were synthesized by the nucleophilic substitution of 4-chlorothieno[2,3-d]pyrimidines with various amines. These compounds were evaluated for antifungal activity against Piricularia oryzae. The preventive effects on Rice blast, Sheath blight, and Cucumber powdery mildew were also determined by pot tests.     

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.     

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.     

The synthesis and antibacterial activity of 3-alkyl derivatives of some pyrimido[4,5-d] pyrimidine

The synthesis of 4,5-diamino derivatives of pyrimidine and pyrimido[4,5-d]pyrimidines is presented. The antibacterial and antifungal activity of the compounds was investigated on nine selected bacterial species, comparing the changes in the chemical structure with increase in the bioactive properties. The investigations have shown that the obtained derivatives of pyrimido[4,5-d]pyrimidines and especially the compounds reveal interesting antibacterial 6e and antifungal 6d 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.     

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidine derivatives as diuretics

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidines 1 and 6,10-dihydro-5H-pyrido[3',2':5,6]pyrimido[2,1-c] [1,2,4]triazines 4 with 5-one, 5-thione or 5-hydrazono substituents and in some cases 1,2,3,4 or 8,9 hydrogenated are synthetized. The diuretic, natriuretic and kaliuretic activities of these compounds in Wistar rats at a dose of 24 mg/kg were estimated. A series of 24 possible derivatives of 1 and 4 possessing diuretic and saliuretic activities are investigated for structure-activity relationships in light of Fujita-Ban model. The Fujita-Ban group contributions have been calculated for different structural variations on the parent ring 1a. It is observed that the hydrogenation of pyridine, [1,3]thiazole or [1,2,4]triazine rings on 1 or 4 decrease the diuretic and saliuretic activities.     

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.     

Antimykotische Wirkstoffe, 11. Mitt. 4-Amino-3-methylpyrazolo[3,4-d]pyrimidine

Antimycotic Drugs, XI: 4-Amino-3-methylpyrazolo[3,4-d]pyrimidines The ring closure of the 5-amino-4-cyano-3-methylpyrazoles 4a-e leading to the 4-amino-3-methyl-pyrazolo[3,4-d]pyrimidines 6a-e has been effected with formamide (5) . Structures of type 4 (4a-h) arise from the interaction of (ethoxyethylidene)malononitrile (1) with the hydrazine derivatives 2a-h via the (hydrazinoethylidene)malononitriles 3 .     

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 properties of 7-methyl-5-oxo-1,5-dihydro-8-[1,2,4]-triazolo [4,3-c]pyrimidinecarboxylic acid derivatives

The synthesis of the new triazolo[4,3-c]pyrimidines is described, starting from derivatives of 5-carboxy-2-hydroxy-4-hydrazino-6-methylpyrimidine. The 4-methyl-2,3-dihydropyrazolo[3,4-d]pyrimidine-3,6-dione was also obtained. Some of triazolo[4,3-c]pyrimidines tested for biological activity were found inactive.     

Reactions of 3-aminopyrazole derivatives with cyanothioacetamide and its derivatives: Synthesis and reactions of several new pyrazole and pyrazole[3,2-b]pyrimidine derivatives

Thiocarboxamidocinnamonitrile derivatives2 a-f reacted with 3-aminopyrazole derivatives3 a-c to give the pyrazole[3,2-b]pyrimidine derivatives6 a-p. Compounds6 a-p were used as starting material for syntheses of several heterocylic coompounds. Dehydrogenation of6 gave pyrazole[3,2-b]pyrimidines10 a-d while its reaction with diethyl oxalate gave11. Reactions of6 with formic acid gave pyrazolopyrimidines17 a-j, and pyrazolopyrimidopyrimidinoes18 a-j.     

Synthesis, antitumor activity, and mechanism of action of benzo[a]pyrano[3,2-h]acridin-7-one analogues of acronycine

Twenty-two derivatives belonging to the cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[a]pyrano[3,2-h]acridin-7-one series were synthesized in nine steps starting from 3,5-dimethoxyacetanilide (5) and 2-methoxy-1-naphthalenecarboxylic acid (7). Most of them exhibited submicromolar cytotoxicity when tested against murine leukemia (L1210) and human epidermoid carcinoma (KB-3-1) cell lines. The cytotoxic activity correlated strongly with the ability of the compounds to form covalent adducts with purified DNA. Among the most active compounds, 25, with IC50 values of 0.7 and 0.15 microM against L1210 and KB-3-1, respectively, was selected for evaluation in vivo against Colon 38 adenocarcinoma implanted in mice. This compound was active at 3 mg/kg i.v. (day 12 and 24) with 3/7 tumor free mice by day 80.