Acyclic Analogues Research Articles

Synthesis, Cytotoxic Activity and Molecular Modelling of Novel [1,2,3]triazolo[4,5-d]pyrimidine Compounds, their Glycoside Derivatives and Acyclic Analogs

Novel substituted [1,2,3]triazolo[4,5-d]pyrimidine-7-one derivatives were synthesized using 1,2,3-triazolo-4-carboxamide derivative (2) by the reaction with carbon disulfide, triethoxymethane, 4-fluorobenzaldehyde and ethyl benzoate respectively. The S-glucoside, N-glycoside derivatives and acyclic sugar analogs of new synthesized [1,2,3]triazolo[4,5-d]pyrimidines were also synthesized. The synthesized compounds were tested for cytotoxicity and in vitro anticancer activity versus human lung (A549), colon (HCT116) and breast (MCF-7) cancer cell lines. The results disclosed that the synthesized compounds apply their activities in A549 and MCF-7. MCF-7 cells are more sensitive to the tested compounds than the other cell lines. Compounds 2, 3, 9 and 10 exposed promising anticancer activities compared to the action of the ordinarily used anticancer drug, doxorubicin in both A549 and MCF-7 cell lines. A good binding affinities for compounds 2, 3, 6, 10 and 11 were noted in docking studies. Results showed a clear effect of N3-substitution in pyrimidine ring on the activities of the synthesized compounds

Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro

All medically important unicellular protozoans cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Therefore, purine derivatives have been considered as a promising source of anti-parasitic compounds since they can act as inhibitors of the PSP enzymes or as toxic products upon their activation inside of the cell. Here, we characterized a Trypanosoma brucei enzyme involved in the salvage of adenine, the adenine phosphoribosyl transferase (APRT). We showed that its two isoforms (APRT1 and APRT2) localize partly in the cytosol and partly in the glycosomes of the bloodstream form (BSF) of the parasite. RNAi silencing of both APRT enzymes showed no major effect on the growth of BSF parasites unless grown in artificial medium with adenine as sole purine source. To add into the portfolio of inhibitors for various PSP enzymes, we designed three types of acyclic nucleotide analogs as potential APRT inhibitors. Out of fifteen inhibitors, four compounds inhibited the activity of the recombinant APRT1 with Ki in single µM values. The ANP phosphoramidate membrane-permeable prodrugs showed pronounced anti-trypanosomal activity in a cell-based assay, despite the fact that APRT enzymes are dispensable for T. brucei growth in vitro. While this suggests that the tested ANP prodrugs exert their toxicity by other means in T. brucei, the newly designed inhibitors can be further improved and explored to identify their actual target(s).

Synthesis of a Seco iso-Secologanin Aglycone Analogue of Interest toward Secoiridoids and Monoterpene Indole Alkaloids.

We report the access to an acyclic iso-secologanin aglycone analogue relevant to secoiridoids and monoterpene indole alkaloids. Its synthesis involved the regioselective allylic alkylation of a linear dienyl carbonate with dimethyl malonate, which was catalyzed by an iridium complex, and an anti-Markovnikov Wacker-type oxidation of the terminal alkene of the branched product that was obtained. The thus-formed aldehyde was engaged in a Pictet-Spengler reaction with tryptamine toward monoterpene indole alkaloids.

Screening and application of a broad-spectrum aptamer for acyclic guanosine analogues

Acyclic guanosine analogues, a class of widely used antiviral drugs, can cause chronic toxicity and virus resistance. Therefore, it is essential to establish rapid and accurate methods to detect acyclic guanosine analogues. In this study, five acyclic guanosine analogues (acyclovir, famciclovir, ganciclovir, penciclovir, and valaciclovir) were used as positive targets to obtain broad-spectrum aptamers through Capture-SELEX technology. Real-time quantitative PCR (Q-PCR) was used to monitor the aptamer SELEX process. After the sixteen rounds of selection against mixed targets, sequences were obtained by high-throughput sequencing (HTS). Furthermore, a broad-spectrum aptamer, named CIV6, was found as the higher performance aptamer that was suitable for five acyclic guanosine analogues by graphene oxide (GO) polarization and fluorescence assay. Finally, the aptamer CIV6 was used to construct GO fluorescence assay to detect five acyclic guanosine analogues. The limits of detection (LOD) of acyclovir, famciclovir, ganciclovir, penciclovir, and valaciclovir were 0.48 ng·mL-1, 0.53 ng·mL-1, 0.50 ng·mL-1, 0.56 ng·mL-1, and 0.38 ng·mL-1, respectively.

Synthetic Opportunities and Challenges for Macrocyclic Kinase Inhibitors.

Macrocycles are typically cyclic variants of inhibitors derived from uncyclized canonical molecules or from natural products. For medicinal chemistry, drug-like macrocycles have received increasing interest over the past few years, since it has been demonstrated that macrocyclization can favorably alter the biological and physiochemical properties as well as selectivity in comparison to the acyclic analogue. Recent drug approvals such as Lorlatinib, glecaprevir, or voxilaprevir underline the clinical relevance of drug-like macrocycles. However, the synthesis of drug-like macrocycles can be challenging, since the ring-closing reaction is generally challenging with yields depending on the size and geometry of the bridging linker. Nevertheless, macrocycles are one opportunity to expand the synthetic toolbox for medicinal chemistry to provide bioactive molecules. Therefore, we reviewed the past literature of drug-like macrocycles highlighting reactions that have been successfully used for the macrocyclization. We classified the cyclization reactions by their type, ring-size, yield, and macrocyclization efficiency index.

Enhanced Gearing Fidelity Achieved Through Macrocyclization of a Solvated Molecular Spur Gear.

Molecular spur gear dynamics with high gearing fidelity can be achieved through a careful selection of constituent molecular components that favorably position and maintain the two gears in a meshed configuration. Here, we report the synthesis of a new macrocyclic molecular spur gear with a bibenzimidazole stator combined with a second naphthyl bis-gold-phosphine gold complex stator to place two 3-fold symmetric 9,10-diethynyl triptycene cogs at the optimal distance of 8.1 Å for gearing. Micro electron diffraction (μED) analysis confirmed the formation of the macrocyclic structure and the proper alignment of the triptycene cogs. Gearing dynamics in solution are predicted to be extremely fast and, in fact, were too fast to be observed with variable-temperature 1H NMR using CD2Cl2 as the solvent. A combination of molecular dynamics and metadynamics simulations predict that the barriers for gearing and slippage are ca. 4 kcal mol-1 and ca. 9 kcal mol-1, respectively. This system is characterized by enhanced gearing fidelity compared to the acyclic analog. This is achieved by rigidification of the structure, locking the two triptycenes in the preferred gearing distance and orientation.

Effect of varying substituent on the colour change transitions of diacetylene pigments

A library of closely related diacetylenes has been synthesised, comprising docosa-10,12-diynediamides with small n-alkyl or cycloalkyl substituents on the termini. Colour changes of these solids in response to ultraviolet (UV) radiation and heating were analysed using a range of analytical techniques, including UV–visible/near-infrared reflectance, hand-held Raman and solid-state nuclear magnetic resonance (ssNMR) spectroscopies. Colorimetric studies showed that this class of diacetylene undergoes clear colour changes that are very sensitive to even small alterations in molecular structure. The colour change transitions of diacetylenes bearing either cyclopentyl or cyclohexyl substituents were more similar to each other than to those of analogous diacetylenes bearing either n-pentyl or n-hexyl substituents. Differential scanning calorimetry (DSC) also reflected these differences, with the cycloalkyl substituted diacetylenes showing endothermic transitions at significantly higher temperatures than both acyclic analogues. From this library, an n-hexyl substituted diacetylene shows the greatest potential as a colour change pigment, with three distinct colours that are stable at room temperature (white, blue, red), as well as an unstable yellow colour at elevated temperatures.

Gas-Phase Rate Coefficient of OH + 1,2-Epoxybutane Determined between 220 and 950 K

Epoxides have many primary and secondary atmospheric sources. As with other oxygenates, they exhibit a complex temperature-dependent reaction with OH, whose full description is necessary in order to understand their interactions in atmospheric and combustion environments. We measured the kinetics of the title reaction using two complementary absolute methods: pulsed-laser photolysis–laser-induced fluorescence (PLP–LIF) and a discharge-flow mass spectrometric system (DF-MS), both monitoring temporal decays in OH. In addition, two relative methods employing the DF-MS as a function of temperature as well as several simulation chamber experiments at room temperature were performed. A very weak negative temperature dependence was observed at T ≤ 285 K, and only through the combination of precise data and a large temperature range were we able to discern the transition toward positive temperature dependence found at T ≥ 295 K. The non-Arrhenius temperature dependence of OH + 1,2-epoxybutane implies the agency of prereactive complexes in this reaction mechanism, albeit with a smaller effect than that with its acyclic ether analogues. This will have implications for understanding the chemical fate of epoxides within oxidizing environments.

Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors.

A new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to C and D rings of a protoberberine core. The reaction conditions were developed to facilitate the formation of sultones with high yields without by-product formation. Thus, it was shown that the order of addition of reagents affects the composition of the reaction products: when sulfochlorides are added to berberrubine, their corresponding 9-O-sulfonates are predominantly formed; when berberrubine is added to pre-generated sulfenes, sultones are the only products. The reaction was shown to proceed stereo-selectively and the cycle configuration was confirmed by 2D NMR spectroscopy. The inhibitory activity of the synthesized sultones and their 12-brominated analogs against the DNA-repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important target for a potential antitumor therapy, was studied. All derivatives were active in the micromolar and submicromolar range, in contrast to the acyclic analogs and 9-O-sulfonates, which were inactive. The significance of the sultone cycle and bromine substituent in binding with the enzyme was confirmed using molecular modeling. The active inhibitors are mostly non-toxic to the HeLa cancer cell line, and several ligands show synergy with topotecan, a topoisomerase 1 poison in clinical use. Thus, novel berberine derivatives can be considered as candidates for adjuvant therapy against cancer.

Method Development and Validation for Estimation of TinofovirDisproxil Fumarate in Pharmaceutical Preparation by UV-Spectroscopy and HPLC With Force Degradation Study

Tinofovir Disoproxil Fumarate (TDF) is an acyclic nucleotide diester analog of adenosine monophosphate from the antiviral category utilized in the AIDS and hepatitis B treatment. In the present study, two analytical methods, i.e. UV and HPLC were developed for the TDF’s estimation in pharmaceutical preparation. In the UV method, the mobile phase used was Methanol and water in 60:40 ratio for estimation of the drug at 260 nm and an assay of the (TDF) obtained was 99.53%. The method’s validation was carried out as per ICH Q2 R1 guidelines in which linearity was detected from 10-50 µg/ml range with a regression value of 0.999 Percent RSD value of accuracy, precision and robustness were below 2. In the HPLC method estimation of (TDF) was evaluated on Cosmosil C-18 (250mm×4.6ID, Particle size: 5 µ) column utilizing Methanol: Water (60:40), 0.9 ml/min of flow rate, detection wavelength was 260 nm and the time of retention observed was around 4.63 minutes with the assay value 99.07%. HPLC method was also validated according to ICH guidelines, where linearity was detected in the 10-50 μg/ml of range with the regression coefficient value 0.999. The % RSD of precision, accuracy, and robustness was below 2%. The study of forced degradation was also performed by the HPLC method utilizing methanol: water (60:40) at 260nm. From this study, it can be concluded that the developed methods for estimation of (TDF) drug in pharmaceutical preparation are simple, accurate, precise, and can be utilized in the routine analysis for quantification of the drug in a dosage form.

Antibiofilm properties of copper (II) and iron (III) complexes with an EDTA-based phenylene macrocycle and its acyclic analogue against food and clinical related pathogens

Bacterial food-borne and nosocomial infections are a public health issue around the world that is exacerbated by biofilm formation and acquired resistance to antibiotics. New therapies focusing on the prevention of biofilm formation may help to face these challenges. In this study, the antibiofilm activity of Cu2+ and Fe3+ complexes formed with an EDTA-based phenylene macrocycle and its acyclic analogue (edtaod and edtabz) was evaluated against Escherichia coli O157: H7, Listeria monocytogenes, Pseudomonas aeruginosa, Salmonella enterica sub. enterica serovar Typhimurium and Staphylococcus aureus. In general, edtabz ligand and complexes, at 0.25–1 mM, presented higher biomass reduction of biofilms than edtaod and its complexes against L. monocytogenes (edtabz and Fe-edtabz; 66.1–99.1% and 78.3–97.4%, respectively), P. aeruginosa (edtabz; 66.4–88.1%), S. aureus (Cu-edtabz; 27.4–73.9%) and Salmonella Typhimurium (Cu-edtabz; 19.4–75.5%). While biofilm formation of E. coli was inhibited by Cu-edtaod with a biomass reduction of 71.5–80.7%. Additionally, antibiofilm activity of edtaod was enhanced by Cu2+ or Fe3+ complexation. Correlation analysis showed that molecular properties such as molecular weight, volume and the number or rotatable bonds have a positive relationship with antibiofilm activity of compounds. Principal component analysis showed that biofilm inhibition patterns of Salmonella Typhimurium, L. monocytogenes and P. aeruginosa were similar and closely related with molecular volume of EDTA complexes. Overall, the results suggest that EDTA-based phenylene macrocycles and its Cu2+ and Fe3+ complexes with its antibiofilm activity can be useful to prevent biofilm related infections.

Carbamoyl Functionalized Bent para-Phenylenes via an Unexpected Reaction of the Burgess Reagent with α-Ketols.

The attempted dehydration of macrocyclic α-ketols with the Burgess reagent has resulted in the unexpected synthesis of carbamoylated, bent para-phenylene units. The same reaction with an acyclic analogue affords the intended dehydration product, indicating that the change in reactivity is conformationally controlled and a result of the bifunctional nature of the Burgess reagent.

Discovery of new TLR7 agonists by a combination of statistical learning-based QSAR, virtual screening, and molecular dynamics

Search for new antiviral medications has surged in the past two years due to the COVID-19 crisis. Toll-like receptor 7 (TLR7) is among one of the most important TLR proteins of innate immunity that is responsible for broad antiviral response and immune system control. TLR7 agonists, as both vaccine adjuvants and immune response modulators, are among the top drug candidates for not only our contemporary viral pandemic but also other diseases. The agonists of TLR7 have been utilized as vaccine adjuvants and antiviral agents. In this study, we hybridized a statistical learning-based QSAR model with molecular docking and molecular dynamics simulation to extract new antiviral drugs by drug repurposing of the DrugBank database. First, we manually curated a dataset consisting of TLR7 agonists. The molecular descriptors of these compounds were extracted, and feature engineering was done to restrict the number of features to 45. We applied a statistically inspired modification of the partial least squares (SIMPLS) method to build our QSAR model. In the next stage, the DrugBank database was virtually screened structurally using molecular docking, and the top compounds for the guanosine binding site of TLR were identified. The result of molecular docking was again screened by the ligand-based approach of QSAR to eliminate compounds that do not display strong EC50 values by the previously trained model. We then subjected the final results to molecular dynamics simulation and compared our compounds with imiquimod (an FDA-approved TLR7 agonist) and compound 1 (the most active compound against TLR7 in vitro, EC50 = 0.2 nM). Our results evidently demonstrate that cephalosporins and nucleotide analogues (especially acyclic nucleotide analogues such as adefovir and cidofovir) are computationally potent agonists of TLR7. We finally reviewed some publications about cephalosporins that, just like pieces of a puzzle, completed our conclusion.

Chemo- and regioselective ring-opening of donor-acceptor oxiranes with N-heteroaromatics.

The first ring-opening of D-A oxiranes with N-heteroaromatics in a chemoselective C-C bond cleavage manner was achieved. In the presence of 5 mol% of Y(OTf)3 as the catalyst, diverse N-heteroaromatics, including benzotriazoles, purines, substituted benzimidazole, imidazole and pyrazole, reacted well with various D-A oxiranes, providing acyclic nucleoside analogues containing a N-glycosidic bond in up to 97% yield and up to >95 : 5 regioselectivity. Through simple transformation, the Ganciclovir analogue could also be obtained.

Between Oxirane and Phosphirane: The Spring‐loaded Oxaphosphirane Ring

AbstractDue to the potential interest of oxaphosphiranes in ring‐opening polymerizations, accurate ring strain energies (RSEs) of a wide variety of oxaphosphirane derivatives was computed, after validation of the optimization method by comparison with reported X‐ray structures. The parent oxaphosphirane exhibits a moderate RSE (22.44 kcal/mol) that is significantly enhanced by κ‐P‐complexation (especially with boranes), the introduction of P=O or P+‐Me groups as well as exocyclic double bonds at the ring carbon, such as 3‐methylene, 3‐imino and 3‐oxo functionalities. However, C3 alkyl substitution or pentacoordination at P in σ5λ5‐oxaphosphirane does not lead to significant variation of RSE. Bicyclic spiro‐oxaphosphirane derivatives show an RSE decrease when the size of the spiro ring increases. A moderate linear correlation between RSE and G(r)/ρ(r) values calculated at the ring critical points and also with the relaxed force constant (k0) for the P−C bond is observed for most oxaphosphiranes. The possibility of ring‐opening polymerization by using better (anionic) nucleophiles in the initiation step can be foreseen from the exergonicity and relatively low barrier of the endocyclic C−O cleavage by nucleophilic attack of methanol, thus underlining the effect of the RSE as driving force compared to acyclic analogs.

Molecular dynamics simulations of acyclic analogs of nucleic acids for antisense inhibition

For antisense applications, oligonucleotides must be chemically modified to be resistant to endogenous nucleases. Until now, antisense oligonucleotide (ASO) analogs have been synthesized and then tested for their ability to duplex with a target nucleic acid, usually RNA. In this work, using molecular dynamics calculations simulations, we systematically tested a series of chemically modified analogs in which the 2-deoxyribose was substituted for by one or two methylene groups on each side of the phosphate backbone, producing four compounds, of which three were previously unknown. We used a 9-mer sequence of which the solution structure has been determined by NMR spectroscopy and tested the ability to form stable duplexes of these acyclic analogs to both DNA and RNA. In only one case out of eight, we unexpectedly found the formation of a stable duplex with complementary RNA. We also applied limitations on end fraying because of the terminal AT base pairs, in order to eliminate this as a factor in the comparative results. We consider this a predictive method to potentially identify target ASO analogs for synthesis and testing for antisense drug development.

Chemical Synthesis of Acyclic Nucleoside Phosphonate Analogs Linked with Cyclic Systems between the Phosphonate and the Base Moieties.

The syntheses of acyclic nucleoside phosphonate (ANP) analogs linked with cyclic systems are described in the present review. The purpose of the review is to report the methodology of ANP analogs and to give an idea on the synthesis of a therapeutic structural feature of such analogs. The cyclopropane systems were mainly prepared by diazomethane cyclopropanation catalyzed by Pd(OAc)2, intramolecular alkylation, Kulinkovich cyclopropanation, and use of difluorocyclopropane, and so forth. The preparation of methylenecyclopropane system was made by diazoacetate cyclopropanation catalyzed by Rhodium followed by addition-elimination reactions. For the preparation of a variety of tethered 1,2,3-triazole systems, 1,3-dipolar cycloaddition between azidealkylphosphonates and propargylated nucleobases was mainly applied. The formation of various phosphonate moieties was achieved via phosphonylation of alkoxide, cross-coupling between BrZnCF2P (O)(OEt)2 with iodoalkens catalyzed by CuBr, Michaelis-Arbuzov reaction with phosphite, and Rh(II)-catalyzed O-H insertion, and so forth.

A Tenofovir-Loaded Glycyrrhetinic Acid-Modified Cationic Liposome for Targeted Therapy of Hepatitis B Virus.

Tenofovir (TFV), an acyclic nucleoside analog, exhibits potent anti-HBV activity. However, poor bioavailability, nephrotoxicity and bone toxicity limit its further clinical application. In this work, a novel tenofovir-loaded glycyrrhetinic acidmodified cationic liposome (TGCL) was prepared for targeted therapy of HBV. The TGCL had an average particle size of 107.39 ± 1.21 nm and an entrapment efficiency of 89.83 ± 2.70% with a positive zeta potential of 37.63 ± 1.22 mV. The results of in vitro indicated that the inhibitory effects on HBsAg, HBeAg and HBV cccDNA of TGCL in HepG2.2.15 cells were significantly better than that of free TFV and non-targeted cationic liposome. In the DHBV-infected duck model, TGCL showed remarkably suppression on DHBV DNA than that of free TFV. Overall, TGCL is a promising formulation of TFV for targeted therapy of HBV.

Synthesis of new symmetric cyclic and acyclic halocurcumin analogues typical precursors for hybridization

It is believed that the synthesis of hybrid molecules containing different biologically relevant moieties would furnish multifunctional drugs with the possible synergism of potential importance for the treatment of cancer, diabetic and Alzheimer diseases. It was envisioned that synthesizing different cyclic and acyclic halocurcumin intermediates would furnish key precursors for hybridization. Thus, starting from vanillin (I) as a naturally occurring compound, several O-haloalkyl derivatives (IIa, IIb and III) have been synthesized and characterized. These derivatives were subjected to Knoevenagel condensation reaction with deferent acyclic and cyclic ketones to afford the corresponding symmetric halocurcumin analogues (IV–VIII). The chemical structures of the newly synthesized curcumin intermediates were confirmed with spectroscopic techniques. These analogues, having primary halogen from both sides, are typical precursors of hybrid curcumin analogues.

Treatment of patients with herpetic infection on the principles of evidence-based medicine

The article summarizes modern approaches to the treatment of patients with herpetic infection based on the principles of evidence-based medicine. The use of technologies and drugs in daily medical practice with proved effectiveness is the main objective of such treatment. The effectiveness of various therapeutic approaches, scientifically based principles of the treatment for patients with this pathology has been analyzed. Combined therapy of herpetic infection should be active, long and include several stages. It is important to take into account the sensitivity of different types of herpes viruses to etiotropic agents and the patient's immune response. Reducing the active replication of the virus, minimizing the likelihood of active virions transmission to the regional ganglia through the use of antiviral therapy, reduction of toxicity, elimination of additional antigenic loads are the main objectives of this treatment. Antiviral drugs - acyclovir and its analogues are used at the first stage. Prolonged intake of acyclovir in suppressive doses within 2–12 months, depending on the disease severity is initiated at the second stage of the treatment. It is also advisable to use immunotherapeutic agents, in particular, preparations of immunoglobulins, recombinant interferons, interferon inducers, while their effectiveness requires further study in modern conditions.Conclusions. Acyclic nucleoside analogues remain one of the important components of modern treatment for patients with herpetic infection. Randomized studies have shown that three antiviral drugs (acyclovir, valacyclovir and famciclovir) are clinically effective. Systemic antiviral drugs partially control the symptoms of genital herpes in primary and recurrent episodes, and are effective as suppressive therapy. Considering the chronic recurrent nature of this infection, its complications and consequences, the combined use of replacement immunotherapy with etiotropic antiviral drugs is possible.