New Synthetic Approaches for Cytotoxic Activity of Novel 1,8‐Naphthyridine Derivatives

A series of substituted 1,8‐naphthyridine derivatives was synthesized as cytotoxic agent by using starting material 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carbohydrazide ( 1 ). Further reactions on compound 1 were processed with different reagents to afford the corresponding 3‐heteraryl‐1,8‐naphthyridine derivatives 2–22 . In vitro cytotoxic activities of new synthesized compounds were assayed against Ehrlich ascites carcinoma, which showed that compounds 3 and 12 had the more potent cytotoxic activity.     

Synthesis of substituted pyrimido[4,5‐b] and [5,4‐c]‐[1,8]naphthyridines

Ethyl 1‐ethyl‐7‐methyl‐4‐oxo‐1,4‐dihydro[1,8]naphthyridine‐3‐carboxylate ( 1 ), precursor of nalidixic acid, has been converted in two steps through ([1,8]naphthyridin‐3‐yl)carbonylguanidine derivatives into substituted pyrimido[4,5‐b] and [5,4‐c][1,8]naphthyridines.     

A novel copper(II) complex with 1,10‐phenanthroline and ciprofloxacin

The X‐ray structure analysis of the title compound, chloro[1‐cyclopropyl‐6‐fluoro‐1,4‐dihydro‐4‐oxo‐7‐(piperazin‐4‐ium‐1‐yl)‐3‐quinolinecarboxylate‐κ²O³,O⁴](1,10‐phenanthroline‐κ²N,N′)copper chloride dihydrate, [CuCl(C₁₇H₁₈FN₃O₃)(C₁₂H₈N₂)]Cl·2H₂O or [CuCl(cfH)(phen)]Cl·2H₂O, where cfH is 1‐cyclopropyl‐6‐fluoro‐1,4‐dihydro‐4‐oxo‐7‐(piperazin‐4‐ium‐1‐yl)‐3‐quinolinecarboxylate and phen is 1,10‐phenanthroline, shows that the geometry around the Cu ion is a slightly distorted square pyramid. Two O atoms of the carbonyl and carboxyl groups of ciprofloxacin and two N atoms of 1,10‐phenanthroline are coordinated to the metal centre in the equatorial plane, and a Cl⁻ ion is coordinated at the apical position. Extensive intermolecular hydrogen bonding produces a supramolecular structure that consists of alternating six‐ and 12‐membered rings.     

Simple and Efficient Synthesis of Novel 3‐Substituted 2‐Thioxo‐2,3‐dihydro‐1H‐benzo[g]quinazolin‐4‐ones and Their Reactions with Alkyl Halides and α‐Glycopyranosyl Bromides

A series of 3‐substituted 2‐thioxo‐2,3‐dihydro‐1H‐benzo[g]quinazolin‐4‐ones 4a – e were synthesized from the reaction of 3‐aminonaphthalene‐2‐carboxylic acid 1 with isothiocyanate derivatives 2a – e . The alkylation of 4a – e with alkyl halides gave 3‐substituted 2‐alkylsulfanyl‐2,3‐dihydro‐1H‐benzo[g]quinazolin‐4‐ones 5a – o . S‐Glycosylation was carried out via the reaction of 4a – e with glycopyranosyl bromides 7a and 7b under anhydrous alkaline conditions. The structure of the compounds was established as S‐nucleoside and not N‐nucleoside. Conformational analysis has been studied by homonuclear and heteronuclear two‐dimensional NMR methods (2D DFQ‐COSY, heteronuclear multiple quantum coherence, and heteronuclear multiple bond correlation). The S site of alkylation and glycosylation was determined from the ¹H and ¹³C heteronuclear multiple quantum coherence experiments.     

Photochemistry of 1‐Cyclopropyl‐6‐fluoro‐1,4‐dihydro‐4‐oxo‐7‐ (piperazin‐1‐yl)quinoline‐3‐carboxylic Acid (=Ciprofloxacin) in Aqueous Solutions

The 1‐cyclopropyl‐6‐fluoro‐1,4‐dihydro‐4‐oxo‐7‐(piperazin‐1‐yl)quinoline‐3‐carboxylic acid (=ciprofloxacin; 1 ) undergoes low‐efficiency (Φ=0.07) substitution of the 6‐fluoro by an OH group on irradiation in H₂O via the ππ* triplet (detected by flash photolysis, λ_max 610 nm, τ 1.5 μs). Decarboxylation is a minor process (≤5%). The addition of sodium sulfite or phosphate changes the course of the reaction under neutral conditions. Reductive defluorination is the main process in the first case, while defluorination is accompanied by degradation of the piperazine moiety in the presence of phosphate. In both cases, the initial step is electron‐transfer quenching of the triplet (k_q=2.3⋅10⁸M ⁻¹ s⁻¹ and 2.2⋅10⁷M ⁻¹ s⁻¹, respectively). Oxoquinoline derivative 1 is much more photostable under acidic conditions, and in this case the F‐atom is conserved, and the piperazine group is stepwise degraded (Φ=0.001).     

Ethyl 1,4‐Dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates by a Tandem SNAr‐Addition‐Elimination Reaction

A series of N‐substituted 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylate esters has been prepared in two steps from ethyl 2‐(2‐chloronicotinoyl)acetate. Treatment of the β‐ketoester with N,N‐dimethylformamide dimethyl acetal in N,N‐dimethylformamide (DMF) gave a 95% yield of the 2‐dimethylaminomethylene derivative. Subsequent reaction of this β‐enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47–82% yields by a tandem S_NAr‐addition‐elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.     

A novel binuclear copper complex incorporating a nalidixic acid derivative displaying a one‐dimensional coordination polymeric structure

The identification of the antibacterial action of nalidixic acid (nx) was central to the development of the quinolone antibacterial compounds. The ability of the nx naphthyridyl ring to interact with and inhibit some proteins has encouraged the investigation of similar structures in the search for more active compounds with less adverse effects. The possibility of structural modification by attachment of other biologically active moieties to the naphthyridyl ring of nx allowed the development of new active antimicrobial molecules. Hydrazone derivatives of nx can be synthesized easily based on the condensation of the hydrazide derivative of nx with the desired aldehyde or ketone. Only a few complexes with nx hydrazone derivatives have been described but for none were the crystal structures elucidated. The synthesis of a new one‐dimensional Cu^II coordination polymer, namely catena‐poly[[copper(II)‐di‐μ‐chlorido‐copper(II)‐{μ‐1‐ethyl‐N′‐[(1H‐imidazol‐4‐yl)methylidene]‐7‐methyl‐4‐oxo‐1,4‐dihydro‐1,8‐naphthyridine‐3‐carbohydrazidato}‐[dimethanolcopper(II)]‐{μ‐1‐ethyl‐N′‐[(1H‐imidazol‐3‐yl)methylidene]‐7‐methyl‐4‐oxo‐1,4‐dihydro‐1,8‐naphthyridine‐3‐carbohydrazidato}] dichloride methanol tetrasolvate], {[Cu₃(C₁₆H₁₅N₆O₂)₂Cl₂(CH₃OH)₂]Cl₂·4CH₃OH}_n, with the (1H‐imidazol‐4‐yl)methylidene carbohydrazide derivative of nalidixic acid (denoted h4imi), is presented and its structure is compared to the density functional theory (DFT) optimized structure of free h4imi. The title structure presents an octahedral Cu^II ion on an inversion centre alternating along a polymer chain with a square‐pyramidal Cu^II ion, with the two Cu^II centres bridged by two chloride ligands. Hydrogen bonds involving chloride counter‐ions and methanol solvent molecules mediate the three‐dimensional packing of the polymer. Comparison of the geometrical results from the structure analysis with those derived from a DFT study of the free ligand reveal the differences that arise upon coordination.     

Synthesis and Antimicrobial Activity of Novel Iminophosphocin Derivatives

Iminophosphocins 8a – 8e and 9a – 9e were synthesized in four‐step reactions via Staudinger reaction. 3‐(Bromomethyl)‐1,2,3,4,5‐pentahydro‐3λ⁵‐naphtho[1,8‐f,g][1,5,3]diazaphosphocin‐3‐one ( 3 ) was prepared by reacting tris(bromomethyl)phosphineoxide ( 1 ) with 1,8‐diaminonaphthalene ( 2 ) in the presence of triethylamine (TEA) in dry tetrahydrofuran (THF), and treated with L‐valine methyl ester ( 4 ) and bis(2‐chloroethyl)amine ( 5 ) in the presence of TEA in dry THF to get 3‐methyl‐2‐[(3‐oxo‐1,2,3,4,5‐pentahydro‐3λ⁵‐naphtho[1,8‐f,g][1,5,3]diazaphosphocin‐3‐yl)methylamino]butanoate ( 6 ) and 3‐[di(2‐chloroethyl)aminomethyl]‐1,2,3,4,5‐pentahydro‐3λ⁵‐ naphtho[1,8‐f,g][1,5,3]diazaphosphocin‐3‐one ( 7 ). The compounds 6 and 7 were treated with trichlorosilane (SiCl₃H) in dry tetrahydrofuran (THF) to form the trivalent P(III) intermediates 8 and 9 , which were further treated with various alkyl azides in dry THF in 55–60°C to afford the title compounds 8a – 8e and 9a – 9e . Their structures were established by multi‐nuclear NMR and mass spectra. All the newly synthesized compounds were found to possess moderate anti‐microbial activity.     

Solvent‐free Synthesis of 2,6‐Dihydroxy‐9H‐purin and Pteridine Derivatives

5,6‐Diaminopyrimidin‐2,4‐diol 1 was reacted with 1,4‐d ‐gluconolactone 2 , 6‐chloro‐4‐cyclopropyl‐7‐floro‐1,4‐dihydro‐1‐oxonaphthalen‐2‐carboxilic acid 4 , (3S)‐9,10‐difloro‐3,7‐dihydro‐3‐methyl‐7‐oxo‐2H‐[1,4]oxazino[2,3,4‐ij]quinolin‐6‐carboxylic acid 6 , and dimethylacetylendicarboxylate to afford 1‐(2,6‐dihydroxy‐9H‐purin‐8‐yl)‐sorbitol 3 , 7‐chloro‐1‐cyclopropyl‐6‐flouro‐3‐(2,6‐dihydroxy‐9H‐purin‐8‐yl)quinoline‐4(1H)‐one 5 , 9,10‐difluoro‐2,3‐dihydro‐6‐(2,6‐dihydroxy‐9H‐purin‐8‐yl)‐3‐methyl‐[1,4]oxazine[2,3,4‐ij]quinoline‐7‐one 7 , and (2,4‐dihydroxy‐6‐oxo‐5,8‐dihydro‐6H‐pteridine‐7‐yiliden)‐acetic acid methyl ester 9 , respectively. The synthesized compounds characterized by IR, ¹H‐NMR, ¹³C‐NMR, GC‐mass, and elemental analysis.     

Synthesis and characterization of new complexes of the type [Ru(CO)2Cl2 (2‐phenyl‐1,8‐naphthyridine‐kN) (2‐phenyl‐1,8‐naphthyridine‐kN′)]. Preliminary applications in homogeneous catalysis

Novel ruthenium (II) complexes were prepared containing 2‐phenyl‐1,8‐naphthyridine derivatives. The coordination modes of these ligands were modified by addition of coordinating solvents such as water into the ethanolic reaction media. Under these conditions 1,8‐naphthyridine (napy) moieties act as monodentade ligands forming unusual [Ru(CO)₂Cl₂(η¹‐2‐phenyl‐1,8‐naphthyridine‐ kN )(η¹‐2‐phenyl‐1,8‐naphthyridine‐kN′)] complexes. The reaction was reproducible when different 2‐phenyl‐1,8‐naphthyridine derivatives were used. On the other hand, when dry ethanol was used as the solvent we obtained complexes with napy moieties acting as a chelating ligand. The structures proposed for these complexes were supported by NMR spectra, and the presence of two ligands in the [Ru(CO)₂Cl₂(η¹‐2‐phenyl‐1,8‐naphthyridine‐ kN )(η¹‐2‐phenyl‐1,8‐naphthyridine‐kN′)] type complexes was confirmed using elemental analysis. All complexes were tested as catalysts in the hydroformylation of styrene showing moderate activity in N,N′‐dimethylformamide. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis,spectral, thermal,DNA interaction and antimicrobial properties of novel Cu(II) heterochelates

Novel dimeric Cu(II) heterochelates were synthesized using 1‐cyclopropyl‐6‐fluoro‐4‐oxo‐7‐piperazin‐1‐yl‐1,4‐dihydro‐quinoline‐3‐carboxylic acid (Cpf) and eight different neutral bidentate ligands. All ligands were characterized by elemental analyses, melting point and IR, ¹H NMR and ¹³C NMR spectra, while heterochelates were characterized by elemental analyses, IR spectra, reflectance spectra, magnetic measurements and thermogravimetric analyses. The DNA interaction and cleavage behaviors of the ligands and corresponding heterochelates were studied by UV–vis absorption titration and gel electrophoresis technique, respectively. The results indicate that heterochelates show larger DNA interaction and cleavage affinity than the ligands. The antimicrobial activities of heterochelates, ligands, cupric nitrate and standard drugs against six bacteria and three fungi were tested. Copyright © 2007 John Wiley & Sons, Ltd.     

Facile and simple synthesis of some new polyfunctionally heterocyclic derivatives incorporating 2‐imino‐2H‐chromene moiety

1,2‐Dihydro‐2‐imino‐6‐(2‐imino‐2H‐chromen‐3‐yl)‐1,4‐diphenyl‐pyridine‐3‐carbonitrile 4 has been synthesized and reacted with ethyl cyanoacetate to yield the new 5‐amino‐1,7‐dihydro‐2‐(2‐imino‐2H‐chromen‐3‐yl)‐7‐oxo‐1,4‐diphenyl‐1,8‐naphthyridine‐6‐carbonitrile 6 , which consider a good and available starting intermediate for synthesis of series of functionalized chromenes. So, the compound 6 was utilized as a key for the synthesis of some new pyrimido[5,4‐c][1,8]naphthyridinones, pyrido[2,3‐c][1,6]naphthyridinones, triazolo[3′,4′:1,6]triazino][5,4‐c][1,8]naphthyridinones, triazolo[2′,3′:1,6]pyrimido[4,5‐c][1,8]naphthyridinones, triazepino[6,5‐c][1,8]naphthyridinone, and triazino[5,4‐c][1,8]naphthyridinones. The structures of these compounds were established by elemental analysis, IR, MS, and NMR spectral analysis. J. Heterocyclic Chem., (2012).     

1H, 13C and 15N NMR spectroscopic characterization of unexpected degradation products of the nifedipine analogue bis(2‐cyanoethyl) 2,6‐dimethyl‐4‐(2‐nitrophenyl)‐1,4‐dihydro‐3,5‐pyridinedicarboxylate

In the course of saponification experiments with bis(2‐cyanoethyl) 2,6‐dimethyl‐4‐(2‐nitrophenyl)‐1,4‐dihydro‐3,5‐pyridinedicarboxylate ( 1 ), an analogue of the calcium channel blocker nifedipine, three unexpected degradation products were isolated. The compounds were identified as 3‐(2‐acetamido‐1‐carboxy‐1‐propenyl)‐1‐hydroxy‐2‐indolecarboxylic acid ( 3 ), 9‐hydroxy‐1,3‐dimethyl‐β‐carboline‐4‐carboxylic acid ( 4 ) and 6‐hydroxy‐2,4‐dimethyl‐5‐oxo‐5,6‐dihydrobenzo[c][2,7]naphthyridine‐1‐carboxylic acid ( 6 ). The structures of these compounds were deduced from one‐ and two‐dimensional ¹H, ¹³C and natural abundance ¹⁵N NMR experiments (¹H,¹H‐COSY, gs‐HSQC, gs‐HMBC, ¹⁵N gs‐HMBC), and corroborated by comparison of their NMR data with the respective data for structurally similar compounds. Copyright © 2002 John Wiley & Sons, Ltd.     

Enoxacin trihydrate

The structure of the title compound, 1‐ethyl‐6‐fluoro‐1,4‐di­hydro‐4‐oxo‐7‐(piperazin‐4‐ium‐1‐yl)‐1,8‐naphthyridine‐3‐carb­oxylate trihydrate, C₁₅H₁₇FN₄O₃·3H₂O, has a zwitterion of enoxacin and three water mol­ecules in the asymmetric unit. The zwitterions form sheets lying parallel to each other and are hydrogen bonded in a head‐to‐tail manner. The crystal structure is stabilized by the involvement of O and H atoms from all the water mol­ecules in strong hydrogen bonds. The naphthyridine ring system is essentially planar, with the carboxyl­ate group lying out of this plane at an angle of 26.13 (6)° and the ethyl group oriented at approximately right angles to this plane. The piperazinium ring adopts a chair conformation.     

Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Pyrazole,Pyridine, and Pyrimidine Derivatives

The starting (1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐yl)carbonohydrazonoyl dicyanide ( 2 ) was used as key intermediate for the synthesis of 3‐amino‐2‐(1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐ylazo)‐[3‐substituted]‐1‐yl‐acrylonitrile derivatives ( 3 – 10 ). In addition, nitrile derivative 2 reacted with hydrazine hydrate or malononitrile to afford the corresponding 3,5‐diaminopyrazole 11 and enaminonitrile derivative 13 , respectively. On the other hand, compound 3 was subjected to react with malononitrile, acetic anhydride, triethylorthoformate, N,N‐dimethylformamide (DMF)‐dimethylacetal, thiourea, and hydroxylamine hydrchloride to afford antipyrine derivatives 16 – 21 . Moreover, the reaction of enaminonitrile 3 with carbon disulfide in pyridine afforded the pyrimidine derivative 22 , whereas, in NaOH/DMF followed by the addition of dimethyl sulphate afforded methyl carbonodithioate 24 . The reaction of enaminonitrile derivatives 3 – 5 with phenylisothiocyanate afforded the thiopyrimidine derivatives 25a – c . Finally, the enaminonitrile 4 reacted with 3‐(4‐chloro‐phenyl)‐1‐phenyl‐propenone to afford the pyridine derivative 27 . The newly synthesized compounds were characterized by elemental analyses and spectral data (IR, ¹³C‐NMR, ¹H–NMR, and MS).     

Mn(III) mixed‐ligand complexes with bis‐pyrazolones and ciprofloxacin drug: synthesis,characterization and antibacterial activities

The fluoroquinolone family member ciprofloxacin is well known for its drug design and coordinating ability towards metal ions. The coordination chemistry of this drug with metal ions of biological and pharmaceutical importance is of considerable interest. Novel Mn(III) mixed‐ligand complexes of ciprofloxacin with various bis‐pyrazolone‐based dinegative bidentate ligands were synthesized and characterized on the basis of their physical properties, magnetic susceptibility measurements, (FT‐IR and electronic) spectral studies. The FAB‐mass spectrum of [Mn(A⁹)(L)(H₂O)₂]·H₂O [where H₂A⁹ = 4,4′‐(p‐tolylmethylene)bis(3‐methyl‐1‐phenyl‐4,5‐dihydro‐1H‐pyrazol‐5‐ol) and HL = 1‐cyclopropyl‐6‐fluoro‐4‐oxo‐7‐(piperazin‐1‐yl)‐1,4‐dihydroquinoline‐3‐carboxylic acid] was determined. All the synthesized compounds were screened for their bioactivity. The mixed‐ligand complexes exhibited comparable activities against two Gram‐negative (Escherichia coli and Serratia marcescens) and two Gram‐positive (Staphylococcus aureus and Bacillus subtilis) microorganisms. Copyright © 2011 John Wiley & Sons, Ltd.     

8‐Fluoro‐4‐hydroxy‐1H‐[1,2,4]triazino[4,5‐a]quinoline‐1,6(2H)‐dione: Synthesis and reactivity

A simple and versatile methodology to synthesise 4‐hydroxy‐1H‐[1,2,4]triazino[4,5‐a]quinoline‐1,6(2H)‐dione from methyl 6‐fluoro‐4‐oxo‐1,4‐dihydro‐2‐quinolinecarboxylate has been developed. It involves car‐bohydrazide formation followed by a condensation with triphosgene to form the fused [1,2,4]triazino ring. In addition, the reactivity of the [1,2,4]triazino ring has been studied.     

Synthesis and Cyclization of 8‐Formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic Acids

A facile synthesis of a series of new quinoline‐8‐carbaldehyde compounds, namely 8‐formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic acids ( 4a – 4h ) and 13‐oxo‐6,13‐dihydro[1]benzoxepino[3,4‐b]quinoline‐8‐carbaldehyde ( 5a – 5g ) is described, involving the one‐pot synthesis reaction of ethyl 2‐(chloromethyl)‐8‐formylquinoline‐3‐carboxylate ( 3 ) with substituted phenols followed by the intramolecular cyclization reaction via the treatment with polyphosphoric acid (PPA). Quinoline‐8‐carbaldehydes 4a – 4h and 5a – 5g are novel and their structures were supported by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis.     

Synthesis and Antimicrobial Studies of Novel Billogical Heterocycles

The synthetic route of sildenafil promoted us to synthesize new object molecules. New analogues containing a 4-thiazolidinone ring bonded to the phenyl moiety at the 2-position, 7-(substituted anilino)-6-fluoro-2-(p-meth- oxy-m-{[2-(p-hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]aminocarbonyl}phenylsulfonamido)benzothiazoles (4a—4l) have been synthesized by cyclization with thioglycollic acid of Schiff bases 3a—3l from corresponding 7-(substituted anilino)-6-fluoro-2-(p-methoxy-m-hydrazinocarbonyl phenylsulfonamido)benzothiazoles (2a—2l). Compounds 2a—2l in turn were prepared by dehydroxyhalogenation followed by condensation with hydrazine hydrates of acids 1a—1l. Compounds 1a—1l in turn were prepared by chlorosulfonation of o-methoxy benzoic acid followed by condensation with 6-fluoro-7-(substituted anilino)-2-aminobenzothiazoles. Final compounds have been characterized by their elemental analysis, IR, NMR and mass spectra. All the synthesized compounds have been screened for their antimicrobial activities. Some of them showed good activities.     

Synthesis of novel fused tricyclic quinolones: 4a,5‐Dihydro‐1H‐[1;2,4]triazino[1,6‐a]quinoline‐2,4,6(3H)‐triones

A versatile methodology to build the 1H‐[1,2,4]triazino[1,6‐a]quinoline‐2,4,6(3H)‐trione structure from methyl 6‐fluoro4‐oxo‐1,4‐dihydro‐2‐quinolinecarboxylate was developed. The method involves an N‐ami‐nation followed by condensation of an aroyl isocyanate to form an alpha semicarbazidocarboxylate that readily cyclizes to the fused [1,2,4]triazino ring under ammonia/ethanol condition. Also, the reactivity of the [1,2,4]triazino ring thus obtained was studied.