Synthesis,characterization and biological activity of Hg(II), Fe(III) complexes with 1,3,4-oxadiazole, 1,2,4-triazole derivatives from L-methionine

Four novel heterocyclic1,3,4-oxadiazole, 1,2,4-triazole derivatives, namely: 5-[1-amino-3-(methylsulfanyl)propyl]-1,3,4-oxadiazole-2(3H)-thione (4), 4-amino-5-[1-amino-3-(methylsulfanyl)propyl]-4H-1,2,4-triazole-3-thiol (5), 1-amino-3-[1-amino-3-(methylsulfanyl)propyl]-1H-1,2,4-triazole-5-thiol (7), and 5-[1-amino-3-(methylsulfanyl)propyl]-1H-1,2,4-triazole-3-thiol (9) have been synthesized from l-methionine and characterized by different spectroscopic techniques (FT-IR, UV–Vis, ¹H NMR, ¹³C NMR and MS). Complex formation with Hg⁺⁺ and Fe⁺⁺⁺ ions were formed from the four heterocyclic 4, 5, 7 and 9. The antimicrobial activities for synthetic intermediates and final four products were assisted using paper disk diffusion method against Gram-negative bacteria: Escherichia coli, Pseudomonas aeroginosae and Gram-positive bacteria: Staphylococus aureus 25923, Staphylococus aureus 43300 and showed variant activity against some of the microorganisms tested.     

Synthesis and thermal behaviour of new benzo-1,2-thiazine long-chain aryl-piperazine derivatives

A series of potential biologically active 2-[3-(4-phenyl-1-piperazinyl)propyl]-3-(4-substituted-benzoyl)-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxides was synthesized in a straightforward manner by condensation of respective 3-substituted-4-hydroxy-1,2-benzothiazine 1,1-dioxides with 1-(1-chloropropyl)-4-phenylpiperazine. The structures of all of the newly formed compounds were identified by elemental analysis, FTIR and ¹H NMR. The synthesized compounds were subjected to preliminary evaluation using differential scanning calorimetry (DSC) to determine the existence of multiple crystal forms. The DSC scans for all compounds show more than one endothermic effect, which might suggest dynamic proton transfer between two or three possible tautomeric forms: O-keto/O-enol, O-enol/O-keto and O-keto/O-keto/CH₂ in crystals 2-[3-(4-phenyl-1-piperazinyl)propyl]-3-(4-substituted-benzoyl)-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxides.     

Synthesis of aryl ω-(1-methyl-5-imidazolyl and 1H-5-tetrazolyl)alkyl ketones

Successful syntheses of 2,4-dichlorophenyl 2-(1-methyl-5-imidazolyl)ethyl and 2,4-dichlorophenyl 3-(1-methyl-5-imidazolyl)propyl ketones are described. In addition, syntheses of 2,4-dichlorophenyl and 4-chlorophenyl 3-(1-methyl-1H-5-tetrazolyl)propyl ketones are reported.     

Synthesis of fluorinated acyclic nucleoside phosphonates with 5-azacytosine base moiety

With respect to the strong antiviral activity of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine various types of its side chain fluorinated analogues were prepared. The title compound, (S)-1-[3-fluoro-2-(phosphonomethoxy)propyl]-5-azacytosine (FPMP-5-azaC) was synthesised by the condensation reaction of (S)-2-[(diisopropoxyphosphoryl)methoxy)-3-fluoropropyl p-toluenesulfonate with a sodium salt of 5-azacytosine followed by separation of appropriate N¹ and O² regioisomers and ester hydrolysis. Transformations of FPMP-5-azaC to its 5,6-dihydro-5-azacytosine counterpart, amino acid phosphoramidate prodrugs and systems with an annelated five-membered imidazole ring, i.e. imidazo [1,2-a][1,3,5]triazine derivatives were also carried out. 1-(2-Phosphonomethoxy-3,3,3-trifluoropropyl)-5-azacytosine was prepared from 5-azacytosine and trifluoromethyloxirane to form 1-(3,3,3-trifluoro-2-hydroxypropyl)-5-azacytosine which was treated with diisopropyl bromomethanephosphonate followed by deprotection of esters. Antiviral activity of all newly prepared compounds was studied. FPMP-5-azaC diisopropyl ester inhibited the replication of herpes viruses with EC₅₀ values that were about three times higher than that of the reference anti-HCMV drug ganciclovir without displaying cytotoxicity.     

Microwave-assisted synthesis and transformations of sterically hindered 3-(5-tetrazolyl)pyridines

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-chloromethyl derivatives. Intramolecular [3+2] cycloaddition of an heteroaromatic cyano group to side azido group was carried out to form a novel heterocyclic system containing a (tetrazolo)azaisoindole unit. Condensation of the 2-methylnicotinonitriles and aldehydes gave rise to the corresponding 2-vinyl derivatives, which were then transformed into novel heterocyclic system (5,6-dihydrotetrazolo[5,1-f]-1,6-naphthyridine) by intramolecular N-alkylation reaction of tetrazole ring with olefinic fragment. The 3-(5-tetrazolyl)pyridines obtained were alkylated to give the various N- and C-benzyl derivatives as well as acylated to afford the 3-(1,3,4-oxadiazol-2-yl)pyridines in good yields. A majority of above-mentioned reactions was carried out under microwave irradiation.     

Regioselective solvent-sensitive reactions of 6-(trifluoromethyl)comanic acid and its derivatives with phenylhydrazine

6-(Trifluoromethyl)comanic acid reacts regioselectively with phenylhydrazine in water to give 5-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-3-carboxylic acid. Similar reaction in dioxane leads to 3-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-5-carboxylic acid. A strong solvent influence on the reaction route was also found for 6-(trifluoromethyl)comanic acid derivatives.     

New silatranes possessing urea functionality: Synthesis, characterization and their structural aspects

The present work aims at the synthesis of various novel silatranes bearing substituted urea functionality. Nucleophilic addition of various amines (morpholine, aniline, ethylenediamine and 3-aminopropyltriethoxysilane) to 3-isocyanatopropyltriethoxysilane resulted in the four triethoxysilanes; N-[3-(triethoxysilyl)propyl]morpholine-4-carboxylic acid amide (1), 1-[3-(triethoxysilyl)propyl]-3-phenylurea (2), 1,2-bis{N′-[3-(triethoxysilyl)propyl]ureido}-ethane (3) and N-[3-(triethoxysilyl)propyl]-N′-[3-(triethoxysilyl)propyl]urea (4), respectively. In the presence of a base the resulting silanes undergo transesterification reaction with triethanolamine, thus forming the corresponding silatranes, N-(3-silatranylpropyl)morpholine-4-carboxylic acid amide (5), 1-(3-silatranylpropyl)-3-phenylurea (6), 1,2-Bis[N′-(3-silatranylpropyl)ureido]-ethane (7) and N-(3-silatranylpropyl)-N′-(3-silatranylpropyl)urea (8), respectively. Among these are four novel compounds (5-8), which were characterized by elemental analysis, IR, multinuclear (¹H, ¹³C and ²⁹Si) NMR and mass spectroscopy. Structures of compounds 5 and 6 were deduced by X-ray crystallography. Single crystal X-ray studies revealed distorted trigonal bipyramidal coordination about Si in 5 and 6 with Si-N bond distance of 2.121(1) Å and 2.189(2) Å, respectively.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-[2-hydroxy-3-(vinyloxy)propyl]oximes and <Emphasis Type="Italic">O</Emphasis>-[(2-methyl-1,3-dioxolan-4-yl)methyl]oximes

By oximes reaction with glycidyl vinyl ether O-[2-hydroxy-3-(vinyloxy)propyl]oximes of ketones and acetaldehyde were synthesized in 54–72% yield, and by acid catalysis the compounds were converted into O-[(2-methyl-1,3-dioxolan-4-yl)methyl]oximes in 61–88% yield.     

Synthesis, structure, and antioxidant activity of hybrid N-substituted salicylic acid amides

Sterically hindered phenols, 3-tert-butyl-N-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-hydroxybenzamide and N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]-2-hydroxybenzamide, were synthesized as potential antioxidants, and the formation of hydrogen bonds by their molecules was shown by UV and IR spectroscopy.     

An unexpected cyclization discovered during the synthesis of 8-substituted purines from a 4,5-diaminopyrimidine

Attempted conversion of 4-chloro-5-(N-4-bromobutanoyl)amino-6-phenethylaminopyrimidine (2) to 6-chloro-8-[1-(3-bromo)propyl]-9-phenethylpurine (1) under standard cyclization conditions did not give the targeted product. Instead, an unexpected cyclization occurred to give 6-chloro-5-[1-(3-hydroxy)propyl]-9-phenethylpurine (3), which can be viewed as a hydrolysis product of the resulting halide. The cyclization reaction was optimized and compound 3 was prepared in excellent yield. A mechanism involving transient generation of a spiro-tetrahydrofuran is also proposed.     

Improved synthetic methods of CP-060S,a novel cardioprotective drug

Two synthetic methods of CP-060S, (−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one (−)-1, have been developed. The first method involved preparative HPLC resolution of bromo-intermediate 4. The second one involved resolution of 1 by crystallization of the corresponding diastereomeric salt.     

A new type of irreversibly reductively biodegradable hydrogel

Reductively biodegradable hydrogels based on poly[N-(2-hydroxypropyl)methacrylamide] crosslinked with N-[3-(methacryloylamino)propyl] -6-{[5-({[3-(methacryloylamino)propyl]amino}carbonyl)-2-pyridyl]disulfanyl}nicotinamide intended for tissue engineering were synthesized and characterized. The rate of irreversible reductive degradation with thiol l-cysteine (a model of human body where several thiols are present in extracellular space) was studied using several l-cysteine concentrations. The mechanism of the irreversible reductive bond cleavage in the crosslinker structure was confirmed on a low-molecular-weight model. The hydrogel is stable during storage in phosphate buffered saline and is degraded relatively quickly in a concentration-dependent manner after addition of l-cysteine to the surrounding medium.     

New dicationic derivatives of dibenzotetraaza[14]annulene: tuning DNA-binding properties

Four new water-soluble derivatives of dibenzotetraaza[14]annulene have been synthesized, bearing meso substituents with different structures and dimensions: 3-(N,N,N-trimethylammonium)propyl, 3-(N-pyridinium-1-yl)propyl, 2-[3-(N,N,N-trimethylammonium)propoxy]benzoyl, and 2-[3-(N-pyridinium-1-yl)propoxy]benzoyl. The crystal structures of 3-(trimethylammonium)propyl and (N,N,N-trimethylammonium)propoxy]benzoyl derivatives were determined by single crystal X-ray analysis. According to the UV-vis titrations, thermal denaturation experiments, and ethidium bromide displacement assays, all compounds presented here interact strongly with double stranded (ct)-DNA. The product equipped with 3-(trimethylammonium)propyl pendant groups and two positive charges interacts with DNA in one dominant binding mode, whereas the other three derivatives revealed more complex mixed-type interactions. The results have been discussed in terms of dimensions, geometry, and electronic properties of the evaluated compounds, on the basis of corresponding crystallographic data.     

Synthesis of the penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)-propyl]amino]benzoyl]-L-glutamic acid (5-DACTHF). An acyclic analogue of tetrahydrofolic acid

The penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]-benzoyl)-L-glutamic acid (1, 5-DACTHF, 543U76) was synthesized by a convergent route. L-γ-Glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid heptakis t-butyl ester ( 20 ) was prepared in ten steps from L-glutamic acid di-t-butyl ester and N-(benzyloxycarbonyl)-L-glutamic acid α-t-butyl ester. 4-[N-[3-(2,4-Diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]trifluoroacetamido]benzoic acid ( 6 ), which was synthesized from pyrimidinylpropionaldehyde 3 in three steps, was condensed with 20 , followed by deprotection to provide N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]benzoyl]-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid ( 2 ). Hexaglutamate 2 is a potent inhibitor of glycinamide ribonucleotide transformylase.     

Ionic liquid-catalyzed and microwave-assisted syntheses of pyrrolizine- and indolizinedione derivatives

3H-Pyrrolo[2,1-a]isoindole-2,5-diones and isoindolo[2,1-a]quinoline-5,11-diones were synthesized by intramolecular cyclization of N-[2-oxo-3-(triphenyl-??⁵-phosphanylidene)propyl]- and N-[2-(triphenyl-??⁵-phosphanylidene)acetyl]phthalimides, respectively, in the presence of ionic liquid ([bmim][BF₄], 10 mol %) as catalyst or under microwave irradiation.     

Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.     

Concise,efficient and highly selective asymmetric synthesis of (+)-(3S,4R)-cisapride

A concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2″′-methoxy-4″′-amino-5″′-chlorobenzamido)piperidine} from commercially available starting materials has been developed. The key step of this synthesis employs the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-[N-3′-(4″-fluorophenoxy)propyl-N-allylamino]pent-2-enoate and in situ enolate oxidation with (?)-camphorsulfonyloxaziridine to set the (3S,4R)-configuration found within the piperidine ring of the product. This synthesis proceeds in 9 steps from commercially available 1-(4′-fluorophenoxy)-3-bromopropane with an overall yield of 19%.     

Structural basis of solid solution formation during chiral resolution

A systematic study of crystal packing in a series of structures is presented: an isostructural triplet of an optically active compound {(R)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile hydrochloride, C₂₂H₃₂ClN₃O₄S} 1, its racemate 2 and their achiral dehydroxy parent compound {2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-[3-(4-morpholinyl)propyl]mercaptoacetonitrile hydrochloride, C₂₂H₃₂ClN₃O₃S} 3. Based on the structures we suggest some requirements necessary for an optically active compound and its racemate to be isostructural. A generally used resolving agent d-champhor sulphonic acid was unable to provide full separation of the racemate. The crystal structure of a partially resolved product (C₃₂H₄₇N₃O₈S₂) 4 sheds light on the possible reasons of this failure. We suggest a few criteria for solid solution formation of diastereomeric salts.     

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part 6: synthesis and incorporation into peptides of the first reported 2,3-dihydroxycyclopentanecarboxylic acid

Herein we report the intramolecular alkylation of nitronates of methyl-5-O-benzyl-3,6-deoxy-6-nitro-β-d-glucofuranoside and methyl-5-O-benzyl-3,6-deoxy-6-nitro-α-d-glucofuranoside into the corresponding 2-oxabicyclo[2.2.1]heptane derivatives. Similarly, methyl-3-O-benzyl-5-deoxy-5-nitromethyl-β-d-xylofuranoside and methyl-3-O-benzyl-5-deoxy-5-nitromethyl-α-d-xylofuranoside were cyclized to (1R,3R,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane and (1R,3S,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane, respectively. These 2-oxabicyclo[2.2.1]heptane derivatives were eventually transformed into enantiopure methyl (1S,2S,3R,4S,5R)-2-amino-2,3-dihydroxycyclopentanecarboxylate and this novel β-amino acid was incorporated into peptides.     

Two novel carbonic acid esters conjugated with oligophenyl glucosides from Rhamnus nakaharai

Two novel carbonic acid esters conjugated with oligomeric phenyl glycosides have been isolated and characterized from the wood of Rhamnus nakaharai. The structures are characterized as 5,7-dihydroxyphthalide 5-O-β-[6-O-{3″-methoxy-4″-O-β-[6?-O-(4?-O-carboxy-3?,5?-dimethoxy)phenyl]glucopyranosyl}phenyl]glucopyranoside (1) and 6-O-{3′-methoxy-4′-O-β-[6″-O-(3?-mercapto-5?-methoxy-4?-O-methylcarboxy)phenyl]glucopyranosyl}phenyl β-glucopyranose (2), namely, rhamnakoside A (1) and B (2), all by NMR and other spectral methods, respectively. They could be a novel case of phase II detoxification products and biogenetic diversity in plant kingdom.