Acyclic Nucleoside Analogues Research Articles

Synthesis and Antimicrobial Activity of New Synthesized Benzimidazole Derivatives and their Acyclic Nucleoside Analogues

A chalcone was prepared by the reaction of 1,4-diacetylbenzene with benzaldehyde. Reaction of this chalcone with cynanothioacetamide/guanidine hydrochloride and malnonitrile in presence of piperdene afforded the corresponding pyridine, pyrimidine, and pyrans derivatives in good yields respectively. Further, bis-chalcone 1 was cyclized to pyrazole analogs by using thiosemicarbazide, semicarbazide and tertiarybutylcarbazate. The newly heterocyclic compounds have been characterized by IR, 1H-NMR and elemental analyses.

Synthesis and Antimicrobial Activity of New Synthesized Benzimidazole Derivatives and their Acyclic Nucleoside Analogues

New benzimidazole derivatives and their N-substituted acyclic nucleoside analogues were prepared. The synthesized compounds were tested for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, Micrococcus, Salmonella typhi and Salmonella para typhi. The synthesized compounds were tested also against fungi species such as Aspergillus flavus, Aspergillus fumigates, Aspergillus ochraceus and Candida albicans. Most of tested compounds exhibited moderate to high antimicrobial activity while few compounds were found to exhibit little or no activity against the tested microorganisms.

Acyclic analogs of nucleosides based on tris(hydroxymethyl)phosphine oxide: synthesis and incorporation into short DNA oligomers

Abstract Tris-(hydroxymethyl)phosphine oxide (THPO) to a certain extent resembles a part of 2′-deoxyribofuranose, although it exists in an acyclic form only and the oxygen atom at the THPO phosphorus center provides additional hydration site or acceptor of hydrogen bonds. After proper protection of hydroxyl groups, THPO was functionalized with nucleobases and converted into phosphoramidite monomers suitable for incorporation into growing oligonucleotide chains within the solid phase synthesis protocol. The resultant THPO-DNA analogs show reduced affinity to complementary DNA strands, and are resistant towards snake venom and calf spleen exonucleases.

Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity.

A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 μM and a CC50 >100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.

Incorporation of an acyclic alkynyl nucleoside analog into siRNA improves silencing activity and nuclease resistance.

In order to improve the silencing activity and nuclease resistance of small interfering RNA (siRNA), we designed and synthesized an acyclic thymidine analog containing 4-pentyne-1,2-diol instead of d-ribofuranose. The incorporation of this analog into siRNAs at specific positions in the strands was found to enhance the silencing activity of siRNAs and to increase the resistance of the siRNA to hydrolytic degradation by a 3' exonuclease.

Synthesis of Novel Saccharide Hydrazones

Synthesis of important heterocyclic hydrazine derivatives N-aminopyrrolidine, N-aminopiperidine, and N-aminoazepane from hydrazine hydrate and dihalogenides were examined and optimized. These heterocyclic hydrazine derivatives were used in condensation reactions with six different monosaccharides to form corresponding hydrazones. Biological evaluations of these novel compounds, which are simple acyclic nucleoside analogs, were done. L-Arabinose N-aminoazepane hydrazone showed minor anti-HIV activity, giving a starting point for further structural modifications.

First enzymatic galactosylation of acyclic nucleoside drugs by β-galactosidase: Synthesis of water-soluble β-D-galactosidic prodrugs

Acyclic nucleoside analogs constitute an important group of antiviral agents. However, these nucleoside drugs suffer from poor water solubility and low oral bioavailability in the clinic use. In the present work, the enzymatic synthesis of the water-soluble galactosidic prodrugs of acyclic nucleosides by using bovine liver β-galactosidase was described. In the enzymatic transgalactosylation between acyclovir (ACV) and o-nitrophenyl β-galactopyranoside (oNPGal), the optimum enzyme dosage, buffer pH, temperature and molar ratio of ACV to oNPGal were 0.225 U/mL, 7.0, 40°C and 2.5, respectively, under which the initial reaction rate and the yield reached 0.40 mM/h and 29%, respectively. In addition, this enzyme could accept ganciclovir (GCV) and penciclovir (PCV) as substrates, affording the corresponding 4’-β-galactosylated derivatives with the yields of 26% and 71%, respectively.

Synthesis of acyclic nucleoside analogues based on 1,2,4-triazolo[1,5-a]pyrimidin-7-ones by one-step Vorbrüggen glycosylation

New acyclovir analogues were obtained by reaction of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones 4a–i with (2-acetoxyethoxy)methyl acetate 5 in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst (Vorbrüggen procedure). Coupling between compounds 4a–f and 5 led to a mixture of N3- and N4-isomers 6 and 7, respectively. On the contrary, the reaction of compounds 4g–i with 5 proceeded selectively with formation of N3-isomers only. It was found that the ratio of 6a–f and 7a–f depends on the presence or the absence of N,O-bis(trimethylsilyl)acetamide (BSA). Glycosylated products 6a–f and 7a–f underwent reversible isomerization under TMSOTf treatment. The ratio of glycosylated products of the coupling reaction between 4 and 5 was thermodynamically controlled. A similar reaction occurred if ZnCl2 was chosen as a catalyst, although lower yields of the acyclic analogues of nucleosides were observed. The glycosylation of other purines (adenine and guanine) can be achieved via the non-BSA modification of the Vorbrüggen procedure.

Cidofovir Treatmenf For Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation For High Risk Hematological Malignancies

Background Hemorrhagic cystitis (HC) is a common cause of morbidity after allogeneic stem cell transplantation (allo-SCT), and symptoms vary from asymptomatic microscopic to frank hematuria with clot formation and urinary tract obstruction. Multiple factors including toxicity of chemo-radiotherapy, BK virus reactivation seems to be involved a in post-transplant HC, nevertheless effective risk factors and treatments of this complication are currently unknown and unresolved. Cidofovir (CDV) is an acyclic nucleoside analogue with a broad range of antiviral activity, including BK virus and thus it has been proposed as treatment for HC after allo-SCT. Methods In this study we retrospectively evaluated 59 consecutive adult patients (median age 45 years) who received CDV for HC after allo-SCT from January 2008 to December 2012 at San Raffaele Hospital. All patients were affected by high risk hematologic malignancies and 39 had active disease at time of transplant. Donors were HLA identical sibling (n=8), family mismatched (n=39), unrelated volunteer (n=11), cord blood (n=1). All patients received a fully myeloablative conditioning regimen, infusion of donor T cells, 25 patients (43%) received also Total Body Irradiation (4 Gray) and in 51 cases (86%) was administered anti-thymocyte globulin as part of the conditioning regimen. BK viral load was determined on urine by TaqMan PCR. CDV was administered at the dose of 5mg/kg/week intravenously (i.v.) in 41 patients and intravescically in 21 patients (4 double treatments). The median dose number of CDV doses was 2 (range 1 to 8). The intravescically route was adopted in case of pending renal insufficiency or impossibility to interrupt intravenous antiviral for concomitant viral reactivations. Results HC occurred in median 14 days after allo-SCT (range -4 to 330). Median duration of symptoms was 34 days (range 6 to 166). At treatment onset 13 patients had grade 0-I HC, 13 grade II, 24 grade III and 9 grade IV. In 55 cases (93%) high BK viral load was detected in urine (BK virus median load 10^7 cp/ml) before treatment. After treatment the reduction of BK viruria was documented in 29 out of 33 evaluable cases (87%), with a 1-log reduction of BK viruria median load (p=0.004). Improvement of HC grade was observed in 41 patients (70%) and a complete clinical response within 7 days from last CDV dose was observed in 30 cases (51%). Worsening of HC leading to urological intervention occurred in 5 treated patients. Four patients died with an ongoing uncontrolled HC: 2 of acute Graft-versus Host Disease, 1 of pneumonia and 1 of relapse. During i.v. CDV treatment 22 out of 41 patients (54%) had a viral reactivation (Cytomegalovirus n=14, Epstein-Barr Virus n=8, Herpes Simplex-1 n=3, Herpes Simplex-6 n=4) and 2 patients developed acute renal failure requiring drug discontinuation. Conclusions CDV treatment after allo-SCT is associated with a reduction of BK viruria load and HC clinical responses in more than half of cases. This is in agreement with data reported in other retrospective trials. Viral reactivations under CDV treatment should be better investigated in the allo-setting, since the long-half life of the drug and its potential nephrotoxicity limits the possibility of concomitant antiviral therapy with other agents. Our data warrant prospective trials to investigate the role of CDV in allo-SCT. Disclosures: Off Label Use: Cidofovir is an acyclic nucleoside analogue with a broad range of antiviral activity, including BK virus and thus it has been proposed as treatment for hemorrhagic cystitis after Allogeneic Stem Cell Transplantation.

Conjugates of 1,2,3-Triazoles and Acyclic Pyrimidine Nucleoside Analogues: Syntheses and X-ray Crystallographic Studies

The synthesis of novel acyclic pyrimidine nucleoside analogues with 1,2,3-triazole ring bound via ethylene spacer or directly to C-5 of pyrimidine ring has been reported. 1,4-Disubstituted 1,2,3-triazoles were synthesized by click chemistry approach using regioselective copper(I)-catalyzed 1,3-dipolar cycloaddition reaction between terminal alkyne and azido pyrimidines under both conventional (method A) and microwave (method B) conditions. N-Alkylation of triazolyl pyrimidines afforded 5-[2-(1,2,3- triazolyl)ethyl]pyrimidine derivatives with penciclovir-, ganciclovir-like and 2,3-dihydroxypropyl side chain, as well as 5-(1,2,3- triazolyl)pyrimidine derivatives with penciclovir- and ganciclovir-like side chain. The stereostructures of 2-hydroxyethyl, 2- tosyloxyethyl, 2-azidoethyl and 4-acetoxymethyl-1,2,3-triazolyl C-5 substituted pyrimidine derivatives were unambiguously confirmed by their X-ray crystal structure analysis. Keywords: Acyclic pyrimidine nucleoside, Azide-alkyne cycloaddition, Click chemistry, 1, 4-disubstituted 1, 2, 3-triazoles, X-ray diffraction, supramolecular assembling.

First-principles DFT study of some acyclic nucleoside analogues (anti-herpes drugs)

Nucleoside analogues (anti-herpes drug) are widely used to combat the Herpes Simplex Virus (HSV). In recent years, there have been efforts to explain the properties and action even of biomolecules, using an accurate first-principles methodology. In this paper, we have studied the properties and successfully explained the effectiveness of anti-herpes drug. Working within the framework of first-principles density functional theory (DFT) using the B3LYP functional and the 6-311+G(d,p) basis set, the structural, electronic properties and thermochemistry of hydrolysis and displacement reactions were determined. Conceptual DFT was used to determine global and local descriptors and intermolecular charge transfer. By comparing the reactivities of the drugs with those of the competing natural nucleoside (dG) during monophosphorylation we show that, as is commonly believed the drugs act by terminating the viral DNA chain.

ChemInform Abstract: Synthesis and Antimicrobial Activity of New Thiazole Derivatives and Their Glucoside and Acyclic Nucleoside Analogues.

AbstractThiazole derivatives, their N‐substituted acyclic nucleoside analogues and substituted glucosides are synthesized and screened for their antimicrobial activities against C.

ChemInform Abstract: Synthesis and Antimicrobial Activity of New Phenytoin Derivatives and Their Acyclic Nucleoside Analogues.

AbstractMost of the newly synthesized compounds exhibit moderate to high antimicrobial activities.

Synthesis and In Vitro Evaluation of Novel Acyclic and Cyclic Nucleoside Analogs with a Thiadiazole Ring

The synthesis of six thiadiazole nucleoside analogs is reported: 5-diacetylamino-1,2,4-thiadiazol-3-one (1), 5-amino-2- (tetrahydrofuran-2-yl)-1,2,4-thiadiazol-3-one (2), 5-amino-3-[(2′-hydroxyethoxy)methyl]-1,3,4-thiadiazol-2-one (3), 5-amino-3-(4′-hydroxy-2′-hydroxymethyl-butyl)-1,3,4-thiadiazole-2-thione (4), (R)-5-amino-3-(2′,3′-dihydroxypropyl)-1,3,4-thiadiazole-2-thione (5), and (S)-5-amino-3-(2′,3′-dihydroxypropyl)-1,3,4-thiadiazole-2-thione (6). The synthesis, characterization, and properties of these new synthesized thiadiazole derivatives are discussed. A dimerization of 5-amino-3H-1,3,4-thiadiazole-2-thione (14) by sodium nitrite resulting in di-(5-amino-1,3,4-thiadiazol-2-yl) disulfide (19) is also reported. The preliminary in vitro evaluation of these newly synthesized compounds is discussed.

Disease Remission in a Horse with EHV‐5‐Associated Lymphoma

Disease Remission in a Horse with <scp>EHV</scp>‐5‐Associated Lymphoma

First and facile enzymatic synthesis of β-fucosyl-containing disaccharide nucleosides through β-galactosidase-catalyzed regioselective glycosylation

β-Galactosidase from bovine liver was purified to homogeneity. Its molecular mass was estimated to be 54kDa by SDS-PAGE, 60kDa by gel permeation chromatography, and 57kDa by matrix-assisted laser desorption ionization – time of flight tandem mass spectrum. This enzyme displayed the highest catalytic efficiency with p-nitrophenyl β-d-galactopyranoside (Vmax/Km value, 0.0173min−1) as the substrate, lower with p-nitrophenyl β-d-fucopyranoside (0.0156min−1) and the lowest with p-nitrophenyl β-d-glucopyranoside (0.0126min−1). With the enzymatic fucosylation of floxuridine as a model reaction, four key reaction conditions were optimized. Under the optimum conditions, the enzymatic synthesis of a group of β-fucosyl-containing disaccharide nucleosides using the purified β-galactosidase was conducted. The desirable 5′-O-β-d-fucosyl derivatives of pyrimidine nucleosides were obtained with 44–60% yields. Besides, the 5′-regioselectivities decreased markedly with increasing bulk of 5-substituents present in the base moiety of nucleosides. In addition, the enzyme could accept acyclic nucleoside analogs as the substrates and catalyze the enzymatic fucosylation of these nucleosides, furnishing the glycosylated products with the yields of 32–36%.

ChemInform Abstract: Synthesis and Antimicrobial Activity of New 1,2,3‐Triazolopyrimidine Derivatives and Their Glycoside and Acyclic Nucleoside Analogues.

AbstractMost of the screened compounds show moderate to high antimicrobial activities.

Synthesis and antimicrobial activity of new phenytoin derivatives and their acyclic nucleoside analogs

New phenytoin derivatives and their N-substituted acyclic nucleoside analogs were prepared. The synthesized compounds were tested for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Streptomyces Sp. Most of the tested compounds exhibited moderate to high antimicrobial activity while a few compounds were found to exhibit little or no activity against the tested microorganisms.

Novel Coumarin Derivatives Containing 1,2,4-Triazole, 4,5-Dicyanoimidazole and Purine Moieties: Synthesis and Evaluation of Their Cytostatic Activity

We report here on the synthesis and in vitro anti-tumor effects of a series of novel 1,2,4-triazole (compounds 3–6), 4,5-dicyanoimidazole (compound 7), and purine (compounds 8–13) coumarin derivatives and their acyclic nucleoside analogues 14–18. Structures of novel compounds 3–18 were deduced from their 1H- and 13C-NMR and corresponding mass spectra. Results of anti-proliferative assays performed on a panel of selected human tumor cell lines revealed that compound 6 had moderate cytostatic activity against the HeLa cell line (IC50 = 35 µM), whereas compound 10 showed moderate activity against the HeLa (IC50 = 33 µM), HepG2 (IC50 = 25 µM) and SW620 (IC50 = 35 µM) cell lines. These compounds showed no cytotoxic effects on normal (diploid) human fibroblasts.

Synthesis and Antimicrobial Activity of New Thiazole Derivatives and Their Glucoside and Acyclic Nucleoside Analogs

New thiazole derivatives were synthesized. The N‐substituted acyclic nucleoside analogs and the substituted glucosides were also prepared. The synthesized compounds were tested for their antimicrobial activity against Candida albicans, Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. The obtained results indicated that most of the tested compounds exhibited low to high moderate activities whereas few compounds were found to exhibit little or no activity against the tested microorganisms.