Synthesis and Antimicrobial Evaluation of Some Novel Pyrido[2,3‐d] Pyrimidine Derivatives and Their Ribofuranosides

2‐Amino‐3‐cyano‐4,6‐disubstituted pyridines 2a–c on treatment with arylisocyanate and arylisothiocyanate afforded 4‐imino‐3,5,7‐trisubstituted pyrido[2,3‐d] pyrimidin‐2(1H)‐ones 3a–c and 4‐imino‐3,5,7‐trisubstituted pyrido[2,3‐d]pyrimidin‐2(1H)‐thiones 4a–c , respectively. The ribofuranosides, namely, 4‐imino‐3,5,7‐trisubstituted‐1‐(2′,3′,5′‐tri‐O‐benzoyl‐β‐d ‐ribofuranosyl) pyrido[2,3‐d]pyrimidin‐2(1H)‐ones 7a–c and 4‐imino‐3,5,7‐trisubstituted‐1‐(2^′,3^′,5^′‐tri‐O‐benzoyl‐β‐D‐ribofuranosyl) pyrido[2,3‐d]pyri‐midin‐2(1H)‐thiones 8a–c , were synthesized by the condensation of trimethylsilyl derivatives of 3a–c and 4a–c with β‐d ‐ribofuranosyl‐1‐acetate‐2,3,5‐tribenzoate. The structure of newly synthesized ribofuranosides and their precursors were established by elemental analyses, IR, ¹H NMR and ¹³C NMR spectroscopy. All the synthesized compounds were screened for their antibacterial and antifungal activities against Escherichia coli, Staphylococcus aureus, Aspergillus niger, and Aspergillus flavus.     

SYNTHESIS AND ANTIMICROBIAL SCREENING OF SOME NEW 4-IMINO-3,5,7-TRISUBSTITUTED PYRIDO[2,3-d]PYRIMIDINES AND THEIR RIBOFURANOSIDES AS POTENTIAL CHEMOTHERAPEUTIC AGENTS

Some new nucleosides, viz. 4-imino-3,5,7-trisubstituted-1-(2′,3′,5′-tri-O-kbenzyl–β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin/e–2(1H)-ones/ thiones(VII/VIII), have been synthesized by condensation of trimethylsilyl derivatives of 4-imino-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin/e-2(1H)-ones/thiones (III/IV) with β-D-ribofuranosyl1-acetate-2,3,5-tribenzoate. Compounds III/IV have been synthesized by refluxing 2-amino-3-cyano-4,6-disubstituted pyridine (II) with substituted an arylisocyanate or an isothiocyanate respectively. The structure of all the synthesized compounds have been established by IR and ¹H NMR studies. These compounds have been screened for antimicrobial activities in order evaluate. The possibility of the derivatives to be used as potential chemotherapeutic agents.     

Reactions with 3,6‐diaminothieno[2,3‐b]‐pyridines: Synthesis and characterization of several new fused pyridine heterocycles

6‐Aminopyridine‐2(1H)thiones 1 reacting with α‐halo‐compounds 2a–c afforded the alkylthiopyridine derivatives 3a–c which in turn cyclized to the corresponding thieno[2,3‐b]pyridine derivatives 4a–c . Several thieno[2,3‐b]pyridine derivatives 7, 16, 19 , pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine derivatives 6a,b, 11a–c, 21 and pyrido[3′,2′:4,5]thieno[3,2‐c]pyridazine derivatives 13, 17 were prepared starting from compounds 4a–c . © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:405–413, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20313     

Syntheses of some new azolopyrido‐[4′,3′:4,5]thieno[2,3‐d]pyrimidines

Diethyl 2‐[(ethoxythioxomethyl)amino]‐4,5,6,7‐tetrahydrothieno[2,3‐c]‐pyridine‐3,6‐dicarboxylate 2 , prepared from diethyl 2‐isothiocyanato‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine‐3,6‐dicarboxylate 1 by boiling in anhydrous ethanol, was converted into pyrido[4′,3′:4,5]thieno[2,3‐d]pyrimidine derivatives 3, 4 by treatment with hydrazine hydrate. The tetracyclic systems imidazo[1,2‐a]pyrido‐[4′,3′:4,5]thieno[2,3‐d]pyrimidine 9 and pyrido[4′,3′:4,5]thieno[2,3‐d][1,3]thiazolo‐[3,2‐a]pyrimidine 10 were synthesized by the reaction of 2 with 1,2‐diaminoethane and aminoethanethiol, respectively. The hydrazino derivative 4 underwent cyclization reactions with orthoesters and nitrous acid to give the corresponding pyrido[4′,3′:4,5]thieno[2,3‐d][1,2,4]triazolo[1,5‐a]pyrimidines 5, 6 and pyrido[4′,3′:4,5]thieno[3,2‐e][1,2,3,4]tetrazolo[1,5‐a]pyrimidine 8 , respectively. Moreover, reactions of 3 with cyanogen bromide, N‐carbethoxyhydrazine, carbon disulfide, and ethylchloroformate resulted in the formation of the new pyrido[4′,3′:4,5]thieno[2,3‐d][1,3,4]thiadiazolo[3,2‐a]pyrimidine derivatives 12–15 . © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:280–286, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10030     

Reactions with dimethylformamide‐dimethylacetal: Synthesis and reactions of several new pyridine and pyrazolo[3,4‐b]pyridine derivatives

6‐Aminopyridine‐2(1H)‐thiones 1a,b reacted with dimethylformamide‐dimethylacetal (DMF‐DMA) to give the corresponding 6‐{[(N,N‐dimethylamino)methylene]amino}pyridine derivatives 2a,b . The latter compounds reacted with hydrazine hydrate to afford the 3,6‐diamino‐1H‐pyrazolo[3,4‐b]pyridine derivative 4 and 3‐amino‐5‐hydrazino‐1H‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine derivative 7 , respectively. Compound 4 condensed with DMF‐DMA to yield the 3,6‐bis{[(N,N‐dimethylamino)methylene]amino}‐1H‐pyrazolo[3,4‐b]pyridine derivative 10 , which reacted with malononitrile to give the corresponding pyridopyrazolopyrimidine derivative 15 . © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:399–404, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20312     

Synthesis of 3‐substituted pyrido[4′,3′:4,5]thieno[2,3‐d]pyrimidines and related fused thiazolo derivatives

Convenient syntheses of 3‐substituted ethyl 4‐oxo‐2‐thioxo‐1,2,3,4,5,6,7,8‐octahydropyrid[4′,3′:4,5]thieno[2,3‐d]pyrimidine‐7‐carboxylates 3a, b, 6, 11–13 , ethyl 3‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5 H‐pyrido[4′,3′:4,5]thieno[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8‐7H‐carboxylate ( 4 ), and ethyl 2‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5H‐pyrido[4′,3′:4,5]thieno[2, 3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8[7H]carboxylate ( 8 ) from diethyl 2‐isothiocyanato‐4,5,6,7‐tetrahythieno[2,3‐c]pyridine‐3,6‐dicarboxylate ( 1 ) are reported. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:201–207, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10131     

Synthesis of 5,7‐Disubstituted 7H‐Pyrrolo[2,3‐d]Pyrimidin‐4(3H)‐ones and Their N‐Alkylation's under Phase Transfer Conditions

5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 were synthesized by the cyclocondensation of 1,4‐disubstituted 2‐amino‐3‐cyanopyrrole 1 with formic acid. When comparative study of N versus O alkylation of ambident 5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 was carried out under liquid–liquid PTC, solid–liquid PTC, and solid–liquid solvent free conditions using various alkylating agents 3 , the N‐alkylated product 4 were obtained selectively and exclusively.     

SYNTHESIS OF SOME 2-THIOXOPYRIDO[2,3-d]PYRIMIDINE RIBOFURANOSIDES AND THEIR ANTIMICROBIAL ACTIVITY

Abstract

2-Thioxc-3,5,7-trisubstitutcd-I-[2′.3′,5′-tri-O-benzoyl-β-D-ribofuranosyllpyrido [2,3-d]pyri midin-4(IH)-ones have been prepared by the condensation of trimethylsilyl derivative of 2-thioxo-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-4(IH)-ones with β-D-ribofuranose 1-acetate-2,3,5-tribenzoate in 65%-78% yield. The structure of the synthesized ribofuranosides and their precursors have been established by IR, ¹H NMR and elemental analysis. These derivatives have been screened for their antimicrobial activity.     

Synthesis of Thiadiazolinylpyrazolopyridine and Pyridopyrazolotriazine Derivatives

3‐Diazotized aminopyrazolo[3,4‐b]pyridines 2a,b used as good synthons for the synthesis of 3‐thiadiazolinylpyrazolo[3,4‐b]pyridines 8a,b through their reactions with thiocyanatoacetophenone ( 6 ) and pyrido[2,3:3′,4′]pyrazolo[5,1‐c][1,2,4]triazines 5a‐d via their reactions with several active methylene containing reagents: 3a,b, 12, 16, 20, 23a‐d and 26a‐c . All the structures of the newly synthesized heterocyclic compounds were established by considering the data of IR,¹H NMR and mass spectra in addition to the synthesis of most newly synthesized heterocyclic compounds via other routes.     

Synthesis and Cytotoxicity of Some Thieno[2,3‐d]pyrimidine Derivatives

A series of compounds 5‐amino‐2‐ethylmercapto‐4‐phenyl‐6‐subistitutedthieno[2,3‐d]pyrimidines ( 8a–d ), 4‐chloro‐7‐ethylmercapto‐9‐phenylpyrimido[5′,4′:4,5]thieno[3,2‐d]triazine ( 9 ), and 2‐ethylmercapto‐8‐oxo‐4‐phenyl‐7‐(4‐chlorophenyl)pyrimido [4′,5′:4,5]thieno[2,3‐d]pyrimidine ( 10 ) were synthesized and their structures were confirmed by ¹H NMR , ¹³C NMR, and MS . All compounds were evaluated for their IC₅₀ values against three cancer cell lines (MCF ‐7, HUH ‐7 and BHK ) and WISH cells. The IC₅₀ of compound ( 8d ) was calculated for each cell line. Interestingly, the IC₅₀ for the normal human amnion WISH cell line was much higher (723 µg/mL) than those found for the tumor cell lines BHK (17 µg/mL), HUH ‐7 (5.8 µg/mL), and MCF ‐7 (8.3 µg/mL). The proliferation inhibition of normal (WISH ) and tumor (BHK , HUH ‐7, and MCF ‐7) cells by compound ( 8d ) was investigated using MTT assay, and the IC₅₀ was calculated after 48 h of treatment for each cell line.     

Syntheses of some new 1,5‐benzothiazepine derivatives and their ribofuranosides as antimicrobial agents

(±)‐cis‐2‐(4‐Methoxyphenyl)‐3‐hydroxy/methoxy‐6‐ethoxy/phenoxy‐2,3‐dihydro‐1,5‐benzothiazepin‐4‐[5H/5‐chloroacetyl/5‐(4′‐methylpiperazino‐1′)acetyl]‐ones have been synthesized by the condensation of 2‐amino‐3‐ethoxy/phenoxybenzenethiol with methyl‐(±)‐trans‐3‐(4‐methoxyphenyl)glycidate in xylene. Ribofuranosides, viz. (±)‐cis‐2‐(4‐methoxyphenyl)‐3‐methoxy‐6‐ethoxy/phenoxy‐2,3‐dihydro‐1,5‐benzothiazepin‐4‐[5‐(2′,3′,5′‐tri‐O‐benzoyl‐β‐D ‐ribofuranosyl)]‐ones, have been synthesized by the treatment of 3‐methoxy derivatives of 1,5‐benzothiazepines with a derivative, sugar, viz. β‐D ‐ribofuranose‐1‐acetate‐2,3,5‐tribenzoate, in toluene in vacuo. The structures of all the synthesized ribofuranosides and their precursors have been characterized on the basis of elemental analyses and IR, ¹H NMR, and ¹³C NMR spectral data. These compounds were screened for their antimicrobial activity. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:620–625, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10051     

Studies with Heterocyclic β‐Enaminoniriles: A Simple Route for the Synthesis of Polyfunctionally Substituted Thiophene,Imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene and Thieno[3,2‐d]pyrimidine Derivatives

Reaction of 3,5‐diaminothiophene‐2‐carbonitrile derivatives 3a‐c with ethoxycarbonylmethyl isothiocyanate and/or N‐[bis(methylthio)methylene]glycine ethyl ester led to formation of 7‐substituted‐8‐amino‐5‐thioxo‐6H‐imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one derivatives 6a‐c and 7‐substituted‐8‐amino‐5‐(methylthio)imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one 7a‐c , respectively. Also, the synthetic potential of the β‐enaminonitrile moiety in 3a‐c has been explored; it proved to be a promising candiate for the synthesis of 1,6‐disubstituted‐2,4‐diamino‐7,8‐dihydro‐8‐oxopyrrolo[1,2‐a]thieno[2,3‐e]pyrimidine derivatives 10a‐f and pyrido[2′,3′:6,5]pyrimido[3,4‐a]benzimidazole derivatives 12a,b .     

Multi‐component Reactions,Solvent‐free Synthesis of Substituted Pyrano‐pyridopyrimidine under Different Conditions Using ZnO Nanoparticles

2‐Amino‐4‐(4‐substitutedphenyl)‐5‐oxo‐4H,5H‐pyrano[2,3‐d]pyrido[1,2‐a]pyrimidine‐3‐carbonitrile‐derivatives 2–12 were synthesized via multi‐component condensation reactions of different aromatic aldehydes, 3H‐pyrido[1,2‐a]pyrimidine‐2,4‐dione 1 , and malononitrile by using ZnO nanoparticles as green chemistry, environmentally friendly catalyst under solvent‐free conditions. The present work creates a variety of biologically active heterocyclic compounds in excellent yield and a short time. The structures of all synthesized compounds were elucidated with the elemental analyses, IR, ¹H NMR, and mass spectral data.     

Three‐Component One‐Pot Synthesis of Indeno[2′,1′:5,6]Pyrido[2,3‐d]Pyrazole Derivatives in Aqueous Media

A series of indeno[2′,1′:5,6]pyrido[2,3‐d]pyrazoles was synthesized by the three‐component reaction of aldehyde, 5‐amino‐3‐methyl‐1‐phenylpyrazole and 1,3‐indenedione in the presence of SDS in aqueous media. The structures were characterized by IR, ¹H NMR, high resolution mass spectra and were further confirmed by X‐ray diffraction analysis.     

Synthesis of Novel Pyridothienopyrimidines,Pyridothienopyrimidothiazines, Pyridothienopyrimidobenzthiazoles and Triazolopyridothienopyrimidines

The reaction of 3‐amino‐4,6‐dimethylthieno[2,3‐b]pyridine‐2‐carboxamide (1a) or its N‐aryl derivatives 1b‐d with carbon disulphide gave the pyridothienopyrimidines 2a‐d , whilst when the same reaction was carried out using N¹‐arylidene‐3‐amino‐4,6‐dimethylthieno[2,3‐b]pyridine‐2‐carbohydrazides (1e‐h) , pyridothienothiazine 3 was obtained. Also, refluxing of 1b‐d with acetic anhydride afforded oxazinone derivative 4 . Compounds 2a and 2b‐d were also obtained by the treatment of thiazine 3 with ammonium acetate or aromatic amines, respectively. When compound 2a was allowed to react with arylidene malononitriles or ethyl α‐cyanocinnamate, novel pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[2,1‐b][1,3] thiazines 5a‐c were obtained. Treatment of 2b‐d with bromine in acetic acid furnished the disulphide derivatives 6a‐c . U.V. irradiation of 2b‐d resulted in the formation of pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[2,1‐b]benzthiazoles 7a‐c . The reaction of 2a‐d with some halocarbonyl compounds afforded the corresponding S‐substituted thiopyrido thienopyrimidines 8a‐j . Compound 8b was readily cyclized into the corresponding thiazolo[3″,2″‐a]‐pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine 9 upon treatment with conc. sulphuric acid. Heating of 2a,b with hydrazine hydrate in pyridine afforded the hydrazino derivatives 11a,b . Reaction of ester 8c with hydrazine hydrate in ethanol gave acethydrazide 10 . Compounds 10 and 11a,b were used as versatile synthons for other new pyridothienopyrimidines 12–15 as well as [1,2,4] triazolopyridothienopyrimidines 16–19.     

First synthesis of novel pentaheterocyclic ring system of 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole

Reaction of 1‐amino‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (1) with dimethylformamide‐dimethylacetal (DMF‐DMA) gave 1 ‐[N,N‐(dimethylaminomethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (2). Compounds (1) reacted with triethylorthoformate yielding 1‐[N‐(ethoxymethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (3). 3‐Amino‐4‐imino‐5‐aryl‐6‐cyanopyrimido[5′,4′:5,6]pyrido[1,2‐α] benzimidazole (4) was synthesized via condensation of either (2) or (3) with hydrazine hydrate. Reactions of (4) with acetic anhydride, ethyl chloroformate or aryl isothiocyanate yielded the respective derivative of the new ring system namely 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole (5–7).     

An Efficient One‐pot Synthesis of Novel Spiro Cyclic 2‐Oxindole Derivatives of Pyrimido[4,5‐b]Quinoline,Pyrido[2,3‐d:6,5‐d′]Dipyrimidine and Indeno[2′,1′:5,6]Pyrido [2,3‐d]Pyrimidine in Water

A novel and facile one‐pot synthesis of spiro cyclic 2‐oxindole derivatives of pyrimido[4,5‐b]quinoline‐4,6‐dione, pyrido[2,3‐d:6,5‐d′]dipyrimidine‐2,4,6‐trione, and indeno[2′,1′:5,6]pyrido [2,3‐d]pyrimidine employing 6‐aminothiouracil (or 6‐aminouracil), isatin, and cyclic 1,3‐diketone (e.g. 1,3‐indanedione, dimedone, or barbituric acid) has been developed.     

Structural Elucidation and Antimicrobial Evaluation of Novel [1,2,4]Triazolo[4,3‐a]pyrimidines and Pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinones

1,3‐Di(thiophen‐2‐yl)prop‐2‐en‐1‐one ( 1 ) was utilized in the synthesis of 4,6‐di(thiophen‐2‐yl)‐3,4‐dihydropyrimidine‐2(1H)‐thione ( 2 ) and 5,7‐di(thiophen‐2‐yl)‐2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐one ( 4 ). The latter thiones were used in the synthesis of two new series of [1,2,4]triazolo[4,3‐a]pyrimidines 10a – i and pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinones 5a – i via reaction with the appropriate hydrazonoyl halides using triethylamine as a basic catalyst in dioxane. The mechanism of formation of the synthesized compounds was discussed, and the assigned structure was established via microanalysis, spectral data (infrared, ¹H NMR, and Mass), and density functional calculations. Moreover, the newly synthesized products were evaluated for their antimicrobial activities, and the results show that some derivatives have been well with mild activities. Finally, quantum chemistry calculations confirmed the mechanism and structure of the products.     

An Efficient Synthesis of Spiro‐oxindole Derivatives by Three‐Component Reactions in Water

An efficient synthesis of (3S)‐1,1′,2,2′,3′,4′,6′,7′‐octahydro‐9′‐nitro‐2,6′‐dioxospiro[3H‐indole‐3,8′‐[8H]pyrido[1,2‐a]pyrimidine]‐7′‐carbonitrile is achieved via a three‐component reaction of isatin, ethyl cyanoacetate, and 1,2,3,4,5,6‐hexahydro‐2‐(nitromethylidene)pyrimidine. The present method does not involve any hazardous organic solvents or catalysts. Also the synthesis of ethyl 6′‐amino‐1,1′,2,2′,3′,4′‐hexahydro‐9′‐nitro‐2‐oxospiro[3H‐indole‐3,8′‐[8H]pyrido[1,2‐a]pyrimidine]‐7′‐carboxylates in high yields, at reflux, using a catalytic amount of piperidine, is described. The structures were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS data) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

An efficient one‐pot synthesis of a new heterocyclic system with high‐fluorescent properties

Nucleophilic substitution of hydrogen in nitro derivative of imidazo[1,2‐a]pyridine has been used as a key step in the one‐pot synthesis of a new highly fluorescent heterocyclic system pyrido [1″,2″:1′,2′]imidazo[4′,5′:5,6]pyrido[2,3‐b]indole. J. Heterocyclic Chem., (2012).