Synthesis and biological activity of some unsaturated 6-azauracil acyclonucleosides

A useful route is described for obtaining Z and E unsaturated alkylating agents 3 and 4. Coupling 6-azauracils 5 and 6 with unsaturated alkylating agent followed by the deprotection with H+ resin gave acyclonucleosides 11-14 in good overall yields. Unsaturated acyclonucleosides phosphonates 19 and 20 were prepared using potassium carbonate as base and 4-bromobut-2-enyl diethyl phosphonate 16 as the alkylating agent. The introduction of a propargyl group at the N-3 position of acyclonucleosides 7, 8 17, 18, 19, and 20 was achieved using potassium carbonate in DMF.     

Synthesis and Absolute Configuration of Pyriculol

A total synthesis of optically active pyriculol is described. The Wittig reaction between an aldehyde 19 and a triphenylphosphonium ylide 12 gave an intermediate 20. Successive treatment of 20 with p-toluenesulfonic acid, active manganese dioxide, and potassium carbonate gave (3′R,4′S)-pyriculol (23), which was identical with natural pyriculol (1) in all respects. From this synthesis, the absolute stereochemistry of pyriculol (1) was determined to be 2-[(3′R,4′S)-3′,4′-dihydroxy- (1′E,5′E)-1′,5′-heptadienyl]-6-hydroxybenzaldehyde     

Synthesis of 2-Bromomethyl-3-Hydroxy-2-Hydroxymethyl-Propyl Pyrimidine and Theophylline Nucleosides Under Microwave Irradiation. Evaluation of Their Activity Against Hepatitis B Virus

Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b–d as well as theophylline (7) with 2,2-bis(bromomethyl)-1,3-diacetoxypropane (2) under microwave irradia-tion gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]-2-methyl-thio pyrmidin-4(1H)-ones 3a–d and 7-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis[(2-(methylthio)-pyrimidin-4(1H)-ones] 4a–c, and 7,7 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis(theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity.     

Synthesis of Acyclovir and HBG Analogues Having Nicotinonitrile and Its 2-methyloxy 1,2,3-triazole

Reaction of pyridin-2(1H)-one 1 with 4-bromobutylacetate (2), (2-acetoxyethoxy)methyl bromide (3) gave the corresponding nicotinonitrile O-acyclonucleosides, 4 and 5, respectively. Deacetylation of 4 and 5 gave the corresponding deprotected acyclonucleosides 6 and 7, respectively. Treatment of pyridin-2(1H)-one 1 with 1,3-dichloropropan-2-ol (8), epichlorohydrin (10) and allyl bromide (12) gave the corresponding nicotinonitrile O-acyclonucleosides 9, 11, and 13, respectively. Furthermore, reaction of pyridin-2(1H)-one 1 with the propargyl bromide (14) gave the corresponding 2-O-propargyl derivative 15, which was reacted via [3+2] cycloaddition with 4-azidobutyl acetate (16) and [(2-acetoxyethoxy)methyl]azide (17) to give the corresponding 1,2,3-triazole derivatives 18 and 19, respectively. The structures of the new synthesized compounds were characterized by using IR, ¹H, ¹³C NMR spectra, and microanalysis. Selected members of these compounds were screened for antibacterial activity.     

Synthesis of Annonaceous Acetogenins from Muricatacin

Synthetic studies of annonaceous acetogenins starting from (?)-muricatacin (1a) or (+)-muricatacin are described, involving (?)-muricatacin (1a), mono-THF acetogenin, solamin (2), reticulatacin (3), (15R, 16R, 19S, 20S)-cis-solamin (4a) and (15S, 16S, 19R, 20R)-cis-solamin (4b), non-adjacent bis-THF acetogenin, 4-deoxygigantecin (5), and epoxide-bearing acetogenin, (15S, 16R, 19S, 20R)-diepomuricanin (6a).     

An Efficient Method for the Synthesis of β-d-Ribonucleosides Catalyzed by Metal Iodides

Abstract

Several β-d-ribonucleosides were synthesized in high yields under mild conditions by N-glycosylations of methyl 2,3,5-tri-O-benzoyl-β-d-ribofuranosyl carbonate (1) with trimethylsilylated nucleoside bases in acetonitrile using a catalytic amount of metal iodide such as SnI₂, SbI₃ or TeI₄. A deprotection of N⁶ -benzoyl group of coupling product took place to a considerable extent when N⁶ -benzoyl-N⁶ , N⁹ -bis(trimethylsilyl)adenine was employed as a nucleoside base using SnI₂ or SnCI₂ as a catalyst while it was minimized when SbI₃ or TeI₄ was used. Further, the N-glycosylation of 1 with 7-trimethylsilyltheophylline in the presence of a catalytic amount of metal iodide was more effectively achieved in nitrile solvents other than acetonitrile.

     

New Acyclic Quinoxaline Nucleosides. Synthesis and Anti-Hiv Activity

A series of acyclonucleosides substituted 1-(4,5-dihydroxypentyl) (13-8) and 2-(4,5-dihydroxypentyloxy)quinoxalines (19-24) were synthesized by the sharpless asymmetric dihydroxylation of the derivatives 1-6 and 7-12, respectively. Treatment of the quinoxaline base 26 with (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate (27) in the presence of NaH/DMF furnished 28. Acid hydrolysis of 28 gave 1-(2,3-dihydroxypropyl)-6,7-dimethyl-quinoxaline-2-one (29). Alternatively, 29 was prepared by sharpless dihydroxylation of 30. All the compounds were evaluated for their in vitro anti-HIV-1 and HIV-2 in MT-4 cell and found inactive, except 29, which showed inhibition of HIV-1 with EC₅₀ value of 0.15 ± 0.1 μg/ml and a therapeutic index (SI) of 73.     

Novel Regioselective Formation of S- and N-Hydroxyl-Alkyls of 5-(3-Chlorobenzo[b]Thien-2-yl)-3-Mercapto-4H-1,2,4-Triazole and A Facile Synthesis of Triazolo-Thiazoles and Thiazolo-Triazoles. Role of Catalyst and Microwave

Regioselective alkylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole (1) with hydroxy alkylating agents 2, 3, 13, and the 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (10) afforded the corresponding S-alkylated derivatives 6, 7, 11, and 14 under both conventional and microwave irradiation conditions; bentonite as a solid support gave better results, with no change in regioselectivity. A facile intramolecular dehydrative ring closure of 6, 7, 11, and 14 using K₂CO₃ in DMF afforded the corresponding fused triazolo-thiazines and thiazolo-triazole 17–19. The isopropylidenes and acetyl derivatives of the products were prepared.     

Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

Synthetic Studies on the Isomeric N -Methyl Derivatives of C-Ribavirin

Abstract

The syntheses of all three of the mono-N-methy1 derivatives of C-ribavirin (3-β-D-ribofuranosyl-1, 2, 4-triazole-5-carboxamide, 2) have been accomplished. Reaction of 1-(β-D-ribofuranosyliminomethyl)-2-methyl-hydrazine ( 7 ) with ethyl oxamate (8) in boiling ethanol gave the N′-methyl-C-ribavirin ( 3 ). A similar treatment of β-D-ribofuranosyl-1-carboximidic acid methyl ester ( 6 ) with N′-methyloxamic hydrazide ( 10 ) furnished the N²-methyl-C-ribavirin ( 4 ). Direct methylation of unprotected 2 with methyl iodide in the presence of potassium carbonate in dimethyl sulfoxide gave N ⁴-methyl isomer ( 5 ) as the major product. Structural assignments of 3 , 4 , and 5 were based on the unequivocal synthetic sequences, ¹H and ¹³C NMR data and confirmed by single crystal X-ray diffraction analysis.     

Synthesis and anticancer activity of some 1,2,3-trisubstituted pyrazinobenzimidazole derivatives

Abstract

The synthesis of some new pyrazino[1,2-a]benzimidazole derivatives and investigation of their anticancer activities were aimed in this work. Thus, 2-acetylbenzimidazole was reacted with appropriate α-bromoacetophenones and potassium carbonate in acetone to give 2-(2-acetyl-1H-benzimidazol-1-yl)-1-phenylethanone derivatives (3a–d). These diketone compounds were reacted with varied benzylamines in acetic acid to obtain 2-benzyl-1-methylidene-3-aryl-1,2-dihydropyrazino[1,2-a]benzimidazole derivatives (4a–t). The structures of the obtained compounds were elucidated by using IR, ¹H-NMR, ¹³C-NMR, MS spectral data and elemental analyses results. Anticancer activities of the selected compounds were investigated in National Cancer Institute, Bethesda, MD. 3c and 4n showed remarkable anticancer activity comparing with standard drugs, melphalan and cisplatin.     

Azinyl sulfides — CXVIII. Antimicrobial activity of novel 1-methyl-3-thio-4-aminoquinolinium salts

Synthesis and antimicrobial activity of novel 1-methyl-3-alkylthio-4-aminoquinolinium salts 2 and 1-methyl-3-acylthio-4-aminoquinolinium salts 4 are described. Compounds 2 were obtained by reacting 1-methyl-3,4-(dimethylthio)quinolinium chloride 1 with amines and by reacting 1-methyl-4-aminoquinolinium-3-thiolates 3 with alkylating agents. Compounds 4 were obtained by the reaction of 1-methyl-4-aminoquinolinium-3-thiolates 3 with acylating agents. Antimicrobial activity of compounds 2 and 4 was determined using G⁺ (Staphylococcus aureus, Enterococcus faecalis) and G⁻ (Escherichia coli, Pseudomonas aeruginosa) strains as well as Candida albicans yeast. The compounds show greatest activity against S. aureus whereas the lowest against P. aeruginosa.     

Study of reactivity of cyanoacetohydrazonoethyl-N-ethyl-N-methyl benzenesulfonamide: preparation of novel anticancer and antimicrobial active heterocyclic benzenesulfonamide derivatives and their molecular docking against dihydrofolate reductase

Abstract

This article describes the synthesis of some novel heterocyclic sulfonamides having biologically active thiophene 3, 4, 5, 6, coumarin 8, benzocoumarin 9, thiazole 7, piperidine 10, pyrrolidine 11, pyrazole 14 and pyridine 12, 13. Starting with 4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-N-ethyl-N-methylbenzenesulfonamide (2), which was prepared from condensation of acetophenone derivative 1 with 2-cyanoacetohydrazide. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR and MS spectral data. All the newly synthesized heterocyclic sulfonamides were evaluated as in-vitro anti-breast cancer cell line (MCF7) and as in-vitro antimicrobial agents. Compounds 8, 5 and 11 were more active than MTX reference drug and compounds 12, 7, 4, 14, 5 and 8 were highly potent against Klebsiella pneumonia. Molecular operating environment performed virtual screening using molecular docking studies of the synthesized compounds. The results indicated that some prepared compounds are suitable inhibitor against dihydrofolate reductase (DHFR) enzyme (PDBSD:4DFR) with further modification.     

Potassium currents in the giant axon of the crabCarcinus maenas

Summary Measurements were made of the kinetic and steadystate characteristics of the potassium conductance in the giant axon of the crabCarcinus maenas. These measurements were made in the presence of tetrodotoxin, using the feedback amplifier concept introduced by Dodge and Frankenhaeuser (J. Physiol. (London) 143:76–90). The conductance increase during depolarizing voltage-clamp pulses was analyzed assuming that two separate potassium channels exist in these axons. The first potassium channel exhibited activation and fast inactivation gating which could be fitted using them ³ h, Hodgkin-Huxley formalism. The second potassium channel exhibited the standardn ⁴ Hodgkin-Huxley kinetics. These two postulated channels are blocked by internal application of caesium, tetraethylammonium and sodium ions. External application of 4 amino-pyridine also blocks these channels.     

Studies on Geobacillus stearothermophilus – Part V: Transformation of 11α-hydroxyprogesterone

The influence of a hydroxyl group on the biotransformation of 11α-hydroxyprogesterone mediated by the thermophile Geobacillus stearothermophilus, was investigated. Bacterial transformation of 11α-hydroxyprogesterone resulted in the formation of previously reported six hydroxylated progesterone metabolites, identified as 11α-hydroxy-5α-pregnane-3, 6, 20-trione 1, 11α, 20α-dihydroxypregnene-3-one 2, 11α, 6β-dihydroxyprogesterone 3, 11α, 6α-dihydroxyprogesterone 4, 11α, 6β, 20α-trihydroxypregnene-3-one 5, 11α, 6α, 20α-trihydroxypregnene-3-one 6. All transformation products were identified through their spectral data and comparison with reference compounds.     

Synthesis,anti-inflammatory,cytotoxic, and COX-1/2 inhibitory activities of cyclic imides bearing 3-benzenesulfonamide,oxime, and β-phenylalanine scaffolds: a molecular docking study

Abstract

Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2–4, and 9), oximes (11–13), and β-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2–82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED₅₀ of 35.4–45.3?mg kg^?1 relative to that of celecoxib (34.1?mg kg^?1). For the cytotoxic evaluation, the selected derivatives 2–6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59–5/59) at 10?μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2–5, and 9), acetophenone oxime (11–14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6–333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives 21–24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46–0.68.     

Synthesis of (Z)- and (E)-9-[(2-Hydroxyethylidene)cyclopropyl]adenine—New Methylenecyclopropane Analogues of Adenosine and Their Substrate Activity for Adenosine Deaminase

Abstract

Synthesis of Z- and E-methylenecyclopropane analogues of adenosine 3 and 4 by alkylation of adenine with novel alkylating agent 5 is described. The E-isomer 4 is a substrate for adenosine deaminase. Compounds 3 and 4 were tested for antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1.     

One‐Pot Solvent Free Synthesis and DNA Binding Studies of Thieno[2,3‐b]‐1,8‐Naphthyridines

Abstract

With the aim of evaluating interaction between double‐stranded calf thymus (ds)DNA and sulphur containing fused planar rings, the derivatives of 1,8‐naphthyridine containing thiono groups were synthesized by the condensation of 2‐mercapto‐3‐formyl[1,8]naphthyridines using 1‐chloroacetone, 2‐chloroacetamide, chloroaceticacid, and 2‐chloro‐1‐phenylethanone in the presence of anhydrous potassium carbonate as s catalyst under solvent free microwave irradiation. The structures of the compounds were elucidated on the basis of elemental analysis, IR, ¹H NMR, and mass spectra. The interaction of thieno[2,3‐b]‐1,8‐naphthyridine‐2‐carboxylic acid (TNC) (3a) with ct‐DNA was studied by UV‐Vis spectrophotometry, viscosity, thermal denaturation, as well as cyclic voltammetry experiments. On binding to DNA, the absorption spectrum underwent bathochromic and hypochromic shifts. Binding parameters, determined from spectrophotometric measurements indicated a binding constant of K _b =2.1×10⁶ M^?1. The thieno[2,3‐b]‐1,8‐naphthyridine‐2‐carboxylic acid (3a) increases the viscosity of sonicated rod‐like DNA fragments. The binding of TNC to DNA increased the melting temperature by about 4°C. The decrease in peak current heights and shifts of peak potential values are observed by the addition of calf thymus DNA in cyclic voltammetry studies.     

Synthesis of Acyclic Nucleoside Using Potassium Iodide as Catalyst

Abstract

An effective method for the synthesis of acyclonucleosides is reported. It is based on the use of potassium iodide as catalyst which enables mild condensation conditions.     

Synthesis,anti-inflammatory,analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC₅₀ value 31.59 μg/mL.