Synthesis and anticonvulsant activity of some 2-(2-{1-[substituted phenyl]ethylidene}hydrazinyl)-4-(4-methoxy-phenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile

A series of dihydro-pyrimidine-5-carbonitrile derivatives (3–16) were synthesized and evaluated for their anticonvulsant activity against MES and scPTZ models. Motor impairment screening was carried out by rotarod test method and CNS depressant effect was determined by Porsolt’s force swim pool method. Compounds 4 and 9 having p-substituted bromo and m-substituted nitro groups, respectively, were found to be most active showing activity both in MES and scPTZ screen at lower doses of 30 mgkg^?1 at 0.5?h and 100 mgkg^?1 at 4?h. In the rotarod motor impairment screen, compound 4 did not show any motor impairment even at the maximum dose of 300 mgkg^?1; however, compound 9 showed motor impairment at 300 mgkg^?1 dose after 4.0?h. The compounds were also tested for their CNS depression effect. The compounds 4 and 9 showed 41.38 and 43.44% increase in immobility time with respect to control. The pharmacophore hypothesis also fits best for compounds 4 and 9.     

Synthesis and bioactivity of 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-oxa(thia)diazol-2-amines

A series of new N′-[N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)thiocarbamoyl]-2-[(1-aryl-1H-tetrazol-5-yl)sulfanyl]acetohydrazides 5a–5e were synthesized rapidly in high yields from 2-(1-aryl-1H-tetrazol-5-ylsulfanyl)acetohydrazides 3a–3e and 2,3,4-tri-O-acetyl-β-d-xylopyranosyl isothiocyanate 4, then 5a–5e were converted to a series of new 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-oxadiazole-2-amines 6a–6e and 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-thiadiazole-2-amines 7a–7e, respectively under mercuric acetate/alcohol system or acetic anhydride/phosphoric acid system, then deacetylated in the solution of CH₃ONa/CH₃OH. All of the novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The structures of compounds 2e, 3e, 5a and 5c have been determined by X-ray diffraction analysis. Some of the synthesized compounds displayed PTP1B inhibition and microorganism inhibition.     

Preparation of enantiomerically pure (R)-(1-hydroxyethyl)dimethyl(phenyl)silane using resting cells of Saccharomyces cerevisiae (DHW S-3) as biocatalyst

The prochiral sila-ketone acetyldimethyl-(phenyl)silane (1) was reduced enantioselectively into (R)-(1-hydroxyethyl)dimethyl(phenyl)silane [(R)-2] using resting cells of the commercially available yeast Saccharomyces cerevisiae (DHW S-3) as the biocatalyst. The bioconversion was performed on a 2.0-g scale in a 5-1 bioreactor. Starting with a substrate (1) concentration of 0.4 g·1^–1, the highest production rate measured for this bioconversion was about 45–55 mol (R)-2·1^–1·min^–1. After an incubation time of 1 h, all substrate in the medium had been converted, either biocatalytically reduced to (R)-2 or (probably chemically) converted into dimethyl(phenyl)silanol (Me₂PhSiOH). After extraction of the cell-free medium with ethyl acetate/dichloromethane and subsequent purification of the extract by Kugelrohr distillation and chromatography on silica gel (medium-pressure liquid chromatography), 800 mg (yield 40%) of the bioconversion product (R)-2 was isolated. As shown by HPLC studies (cellulose triacetate as the chiral stationary phase) and ¹H-nuclear magnetic resonance experiments (after derivatization of the bioconversion product with a chiral auxiliary agent), compound (R)-2 was almost enantiomerically pure (> 99% enantiomeric excess).This article is dedicated to Prof. Dr. Fritz Wagner on the occasion of his 65th birthday     

Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph₃P/Py/NH₄OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N¹-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Identification ofS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-3-mercaptopyruvic acid with a metabolic intermediate betweenS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-l-cysteine andS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-3-mercaptolactic acid

Summary S-[2-Carboxy-1-(1H-imidazol-4-yl)ethyl]-3-mercaptopyruvic acid (I) was chemically synthesized in 15% yield by incubating a reaction mixture oftrans-urocanic acid and 3-fold excess of 3-mercaptopyruvic acid at 45°C for 6 days. The synthesized compound was characterized by fast-atom-bombardment mass spectrometry and high-voltage paper electrophoresis. CompoundI was identified with a product of an enzymatic reaction ofS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-l-cysteine (II) with rat liver homogenate in a phosphate buffer, pH 7.4. CompoundI was degraded toS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-3-mercaptolactic acid (III), a compound previously found in human urine [Kinuta et al. (1994) Biochem J 297: 475–478], by incubation with rat liver homogenate. From these results, we suggest that compoundI is a metabolic intermediate for the formation of compoundIII from compoundII. The present pathway follows a formation of compoundII fromS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl] gluthathione [Kinuta et al. (1993) Biochim Biophys Acta 1157: 192–198], a proposed metabolite ofl-histidine.     

Synthesis and Antiviral Evaluation of Adenosine-N1-Oxide and 1-(Benzyloxy) Adenosines

Abstract

The antiviral activity of adenosine-N¹-oxide (1) and a variety of substituted 1-(benzyloxy) adenosines (2) has been re-investigated and significant in vitro activity vs. Vaccinia virus has been shown. In vivo activity in mice has also been demonstrated.     

An Improved Synthesis of N6-(6-Aminohexyl)FAD

Abstract

We report an improved synthesis of N ⁶-(6-aminohexyl)FAD (1) using an efficient one-pot conversion of inosine to the N-trifluoroacetyl protected N ⁶-(6-aminohexyl)adenosine 3. The 5′-O-phosphorylated AMP derivative 4, activated as the imidazolide, was coupled with commercial sodium riboflavin phosphate by using 18-crown-6 in DMF.     

Stereoselective microbial reduction of N-(4-(1-oxo-2-chloroacetyl ethyl) phenyl methane sulfonamide

Several microbial cultures were screened for the ability to catalyse the reduction of N-(4-(1-oxo-2-chloroacetyl ethyl) phenyl methane sulfonamide (1). The chiral intermediate (+)N-(4-(1-hydroxy-2-chloroethyl) phenyl methane sulfonamide (2) was prepared by the stereoselective microbial reduction of the parent ketone 1. Compound 2 is a potential chiral intermediate for synthesis of 4-(2-isopropylamino-1-hydroxyethyl) phenyl methanesulfonanilide (d-sotalol), a beta-receptor antagonist. Microorganisms from the genera Rhodococcus, Nocardia, and Hansenula reduced 1 to 2. A reaction yield of >50% and optical purities of >90% were obtained. The best strain (H.polymorpha ATCC 26012) effectively reduced compound 1 to compound 2 in 95% reaction yield and 99% optical purity. Compound 2 (8.2 g) was isolated from a 3-1 preparative batch in 68% overall yield. Isolated compound 2 had a specific rotation of +20° (CH₂Cl₂, C-1), an optical purity of 99.5%, and a chemical purity of 97% as analyzed by gas chromatography and HPLC. The nuclear magnetic resonance and mass spectra of compound 2 prepared by bioreduction and a standard chemical sample of 2 were virtually identical. Cell extracts of H. polymorpha in the presence of glucose dehydrogenase, glucose and nicotinamide adenine dinucleotide (NAD ⁺) catalyzed the reduction of 1 to 2 with 98% reaction yield and resulted in an optical purity of 99.4%. Correspondence to: R. N. Patel     

CALB-catalyzed kinetic resolution of (RS)-3-benzoylthio-2-methylpropyl azolides: kinetic and thermodynamic analysis

Abstract

Zofenopril as an ACE inhibitor expired recently was found to have a favourable safety profile in comparison with other ACE inhibitors in treating high blood pressure, congestive heart failure, and acute myocardial infarction. It can be synthesised from the key building blocks of (S)-3-benzoylthio-2-methylpropanoic acid and (4S)-phenylthio-L-proline. In this report, an efficient hydrolytic resolution via Candida antarctic lipase B (CALB) for preparing the former block in isopropyl ether (IPE) containing (RS)-3-benzoylthio-2-methylpropyl pyrazolide (1) and water was developed. Quantitative improvements of the enzyme activity and enantioselectivity in terms of k_2SK_mS^?1?=?5.726?L h^?1 g^?1 and E?=?217 at 45?°C were found from the kinetic analysis. Insights into the CALB performance via thermodynamic analysis were then addressed and compared with those by using (RS)-3-benzoylthio-2-methylpropyl 1,2,4-triazolide (2) as the substrate. A putative thermodynamic model was moreover hypothesised for elucidating the more enthalpy reduction of 68.92-70.86?kJ mol^?1 from the acyl part of (S)-1 and (S)-2 as well as that of 23.69-25.63?kJ mol^?1 from the triad imidazolium to Ser105 and leaving 1,2,4-triazole moiety of (R)-2 and (S)-2 on stabilising the corresponding transition states.     

Synthesis of some new antibacterial active cadmium and mercury complexes of 4-(3-(2-(4-(dimethyl aminophenyl allylidene aminopropyl-imino)prop-1-ethyl)-N,N-dimethyl benzene amine

Abstract

A series of novel cadmium(II) and mercury(II) halide and thiocyanate complexes with an asymmetric Schiff base ligand of 4-(3-(2-(4-(dimethyl aminophenyl allylidene aminopropyl-imino)prop-1-ethyl)-N,N-dimethyl benzene amine has been synthesised and characterised using spectral, physical and analytical data, such as ¹H NMR, UV-Vis and FTIR spectroscopy, melting point, elemental analysis and molar conductivity measurements. The spectral and physical data proposed a pseudo-tetrahedral geometry around the metal centre in the metal complexes. Moreover, the in vitro antibacterial activity of all compounds was assayed against two gram-positive and two gram-negative bacterial strains by a disk diffusion method and the results showed that all compounds have antibacterial characteristics. Also, the minimum inhibitory concentration and minimum bactericidal concentration of each compound were determined.     

2-(R-1H-Benzoimidazol-2-yl)-6-(1-aryliminoethyl)pyridyliron(II) dichlorides: Synthesis, characterization and the ethylene oligomerization behavior

Iron(II) dichloride complexes bearing 2-(methyl-substituted 1H-benzoimidazol-2-yl)-6-(1-aryliminoethyl)pyridines (Fe1–Fe6) or 2-(chloro-substituted 1H-benzoimidazol-2-yl)-6-(1-aryliminoethyl)pyridines (Fe7–Fe12) were synthesized and characterized by FT-IR and elemental analysis. Single crystal X-ray crystallographic analyses revealed that complexes Fe2 and Fe3 possessed a distorted square-pyramidal geometry at iron. Upon activation with either MAO or MMAO, all iron pro-catalysts showed good activities toward ethylene oligomerization with high selectivity for α-olefins and high K values. The influence of the reaction conditions and the nature of the ligands on the catalytic performance of these iron complexes were investigated.     

Synthesis and Antiviral Evaluation of Analogs of Adenosine-N 1-Oxide and 1-(Benzyloxy)Adenosine

Abstract

The activity of a series of compounds related to adenosine-N ¹-oxide (1) and 1-(benzyloxy)adenosine (42) against vaccinia virus has been determined both in vitro and in a vaccinia mouse tailpox model. Significant activities have been found both in vitro and in vivo for a number of the synthetic compounds.     

Syntheses of 1-[2-(Phosphonomethoxy)Alkyl]Thymine Monophosphates and an Evaluation of their Inhibitory Activity Toward Human Thymidine Phosphorylase

A series of new monophosphates of 1-[2-(phosphonomethoxy)alkyl]thymines, such as PMPTp_, 3-MeO-PMPTp, HPMPTp, and FPMPTp, were synthesized and tested for their ability to inhibit human thymidine phosphorylase. Kinetic measurements of enzyme activity were performed using thymidine and inorganic phosphate as the substrates. The data show that some monophosphates provide a considerable increase of the multisubstrate inhibitory effect. The highest inhibitory potency was found with (R)-FPMPTp 4c (K _i ^dT = 4.09 ± 0.47 μM, K _i(P_i) = 2.13 ± 0.29 μM) and (R) 3-MeO-PMPTp 4d (K _i ^dT = 5.78 ± 0.71 μM, K _i(P_i) = 2.71 ± 0.37 μM).     

Biosynthesis of Resorcylic Acid Lactone (5S)-5-Hydroxylasiodiplodin in Lasiodiplodia theobromae

An administration study of ²H-labeled precursors showed that the 9-hydroxydecanoyl unit, the acyl intermediate of lasiodiplodin (1), was also the intermediate of (5S)-5-hydroxylasiodiplodin (2) in Lasiodiplodia theobromae. The incorporation of [O-methyl-²H₃]-lasiodiplodin (6) into 2 indicated that hydroxylation at C-5 occurred after cyclization.     

Synthesis of 3′-O2-(Azaheterocycle)-Thymidines

Abstract

The synthesis of 3′-O ²-(azaheterocycle)-thymidines is presented from 1-thia-3-aza-1,3-butadiene precursors (N-thioacylamidines). A variety of heterocycles is accessible using the dienic, the electrophilic or the nucleophilic reactivity of these thia-azabutadiene systems. 3′-O ²-(azaheterocycle)-thymidine analogues are regarded as potential substrates to interfere with the DNA-polymerization process.     

Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives

Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a–3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H-imidazolidine-2-imines (1a–1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R₁ are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4-methyl and 4-chloro substitution is tolerated as R₁, whereas 4-chloro and 2-methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds.     

Synthesis and biological evaluation of tricarbonyl Re(I) and Tc(I) complexes anchored by poly(azolyl)borates: application on the design of radiopharmaceuticals for the targeting of 5-HT<Subscript>1A</Subscript> receptors

The building blocks fac-[^99mTc{κ³-HB(tim^Me)₃}(CO)₃] and fac-[^99mTc{κ³-R(μ-H)B(tim^Me)₂}(CO)₃] [R is H (4a), Ph (5a); tim^Me is 2-mercapto-1-methylimidazolyl] were obtained almost quantitatively by reacting fac-[^99mTc(CO)₃(H₂O)₃]⁺ with the corresponding scorpionate. These compounds cross the intact blood–brain barrier in mice, with significant retention in the case of 4a and 5a. Using 4a as the lead structure, we have synthesized the functionalized complexes fac-[M{κ³-H(μ-H)B(tim^Bu-pip)₂}(CO)₃] [M is Re (8), ^99mTc (8a); tim^Bu-pip is methyl[4-((2-methoxyphenyl)-1-piperazinyl)butyl](2-mercapto-1-methylimidazol-5-yl)methanamide] and fac-[M{κ ³-H(μ-H)B(tim^Me)(tim^Bu-pip)}(CO)₃] [M is Re (9), ^99mTc (9a)] and evaluated their potential as radioactive probes for the targeting of brain 5-HT_1A serotonergic receptors. The Re complexes exhibit excellent affinity [IC₅₀=0.172 ± 0.003 nM (8); IC₅₀=0.65 ± 0.01 nM (9)] for the 5-HT_1A receptor. The radioactive congeners (^99mTc) have shown an initial brain uptake of 1.38 ± 0.46%ID g⁻¹ (8a) and 0.43 ± 0.12%ID g⁻¹ (9a), but suffer from a relatively fast washout.     

2′-C-Cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine (CNDAC): A Mechanism-Based DNA-Strand-Breaking Antitumor Nucleoside1

Abstract

The antitumor mechanism of action of 2′-C-cyano-2′-deoxy-1-β-d-arabinofuranosylcytosine (CNDAC) has been examined. CNDAC was designed as a potentially DNA-self-strand-breaking nucleoside. It had potent antitumor effects against various solid tumors in vitro as well as in vivo. Using a chain-extension method with Vent (exo^?) DNA polymerase and a short primer/template system, we found that 5′-triphosphate of CNDAC (CNDACTP) was incorporated into the primer at a site opposite a guanine residue in the template. After further chain-extension reaction of the primer containing CNDAC at the 3′-terminus, chain elongation was not observed. Therefore, CNDACTP appeared to act as a chain-terminator. Analyses of the structure of the 3′-terminus in the primer revealed 2′-C-cyano-2′,3′-didehydro-2′,3′-dideoxycytidine (ddCNC) together with CNDAC and 2′-C-cyano-2′-deoxy-1-β-d-ribofuranosylcytosine (CNDC). The existence of ddCNC in the 3′-end of the primer would be due to the self-strand-break by the nucleotide incorporated next to CNDAC. We also found that CNDAC was epimerized to CNDC in near-neutral to alkaline media. Therefore, CNDC found in the primer was epimerized after incorporation of CNDACTP into the primer. We also described the metabolism of CNDAC.     

Synthesis and antileishmanial evaluation of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazole derivatives

A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a–g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a–g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC₅₀ values ranging from 15 to 60 μM. The reference drug pentamidine presented IC₅₀ = 10 μM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.     

Synthese Regiospecifique d'Un Dinucleoside Ponte: (O6 Desoxyguanosnyl)-1(N4-desoxycytidyl)-2 Ethane

Abstract

Appropriate protected deoxyguanosine and deoxyuridine derivatives, respectively activated at 0⁶ and. 0⁴ positions by the 3-nitro 1,2,4-triazol 1-yl group, were reacted with ethylene gtycol, ethylenediamine or ethanolamine to give monoalkylated nucleosides or cross-linked dimers or cross-linked dinucleosides.