Uracil Moiety Research Articles

A Brief Review on the Synthesis of 4H‐Chromene‐Embedded Heterocycles

AbstractChromenes are an essential class of oxygen‐containing heterocyclic compounds with intriguing biological activity. It is an important moiety for the discovery of new drug candidates. Chromenes are naturally abundant as alkaloids, tocopherols, flavones, and anthocyanins. The incorporation of 4H‐chromene, along with various bioactive heterocycles such as indole, pyrazole, kojic acid, pyran‐2‐one, quinoline, pyridine, pyrimidine, coumarin, sesamol, furan, uracil, benzoimidazole, benzotriazole, thiazole, isoxazole and barbituric acid moieties, into a molecular scaffold has the potential to combine the properties of both components. The synergistic effect of combining different heterocyclic moieties within a 4H‐chromene nucleus results in the formation of valuable compounds with significant biological importance. This review summarizes the different synthetic techniques used for preparing 4H‐chromene‐embedded heterocycles. The common mechanisms of key reactions and the significance of the method are discussed.

Design, Synthesis of Novel Pyrido[2,3-d] pyrimidine Derivatives as SARS-CoV-2 Mpro Inhibitors for COVID-19 Therapy

Some of the interesting pyrido[2,3-d] pyrimidines (3a, 3b), 4, (5a–d), (6a, b), 7–13, and (15a–c) based on uracil moiety were synthesized efficiently using a conventional method and ultrasonic irradiation. Heterocyclic scaffolds such as pyrido[2,3-d] pyrimidines are vital structural elements in drug discovery. Their interactions with different viral mechanistic pathways will be leveraged in future research to create heterocycle-based antivirals. Therefore, the purpose of this work is to demonstrate the anticipated contribution of heterocyclic scaffolds to the advancement and identification of SARS CoV-2 treatment, The newly synthesized compounds were characterized by spectral data, and screened for their binding activity toward the main protease of COVID-19 utilizing a molecular docking study, according to the outcome of our initial screening and docking study, the produced compounds 3a, 4, 6a, 13, 15b, and 15c achieved an evaluation in vitro using the SARS-CoV-2 Mpro utilizing the main protease assay, the results of the evaluation showed that the hydrazinylpyridopyrimidine 4 (IC50 value: 10.69 µM) and triazolopyrimidin 15c (IC50 value 8.723 µM) had the greatest inhibitory effects on SARS-CoV-2 Mpro. Additionally, this study was conducted to assess the inhibitory efficacy of the synthesized compounds 4 and 15c, which show moderate inhibition for the replication of SARS CoV-2. Additional molecular dynamics and docking simulations were performed to prove the binding mechanism of 15c.

Photophysics of a nucleic acid-protein crosslinking model strongly depends on solvation dynamics: an experimental and theoretical study.

We present a combined experimental and theoretical study of the photophysics of 5-benzyluracil (5BU) in methanol, which is a model system for interactions between nucleic acids and proteins. A molecular dynamics study of 5BU in solution through efficient DFT-based hybrid ab initio potentials revealed a remarkable conformational flexibility - allowing the population of two main conformers - as well as specific solute-solvent interactions, which both appear as relevant factors for the observed 5BU optical absorption properties. The simulated absorption spectrum, calculated on such an ensemble, enabled a molecular interpretation of the experimental UV-Vis lowest energy band, which is also involved in the induced photo-reactivity upon irradiation. In particular, the first two excited states (mainly involving the uracil moiety) both contribute to the 5BU lowest energy absorption. Moreover, as a key finding, the nature and brightness of such electronic transitions are strongly influenced by 5BU conformation and the microsolvation of its heteroatoms.

Transformation of Algal Toxins during the Oxidation/Disinfection Processes of Drinking Water: From Structure to Toxicity.

With the increase of algal blooms worldwide, drinking water resources are threatened by the release of various algal toxins, which can be hepatotoxic, cytotoxic, or neurotoxic. Because of their ubiquitous occurrence in global waters and incomplete removal in conventional drinking water treatment, oxidation/disinfection processes have become promising alternative treatment options to destroy both the structures and toxicity of algal toxins. This Review first summarizes the occurrence and regulation of algal toxins in source water and drinking water. Then, the transformation kinetics, disinfection byproducts (DBPs)/transformation products (TPs), pathways, and toxicity of algal toxins in water oxidation/disinfection processes, including treatment by ozonation, chlorination, chloramination, ultraviolet-based advanced oxidation process, and permanganate, are reviewed. For most algal toxins, hydroxyl radicals (HO•) exhibit the highest oxidation rate, followed by ozone and free chlorine. Under practical applications, ozone and chlorine can degrade most algal toxins to meet water quality standards. However, the transformation of the parent structures of algal toxins by oxidation/disinfection processes does not guarantee a reduction in toxicity, and the formation of toxic TPs should also be considered, especially during chlorination. Notably, the toxicity variation of algal toxins is associated with the chemical moiety responsible for toxicity (e.g., Adda moiety in microcystin-LR and uracil moiety in cylindrospermopsin). Moreover, the formation of known halogenated DBPs after chlorination indicates that toxicity in drinking water may shift from toxicity contributed by algal toxins to toxicity contributed by DBPs. To achieve the simultaneous toxicity reduction of algal toxins and their TPs, optimized oxidation/disinfection processes are warranted in future research, not only for meeting water quality standards but also for effective reduction of toxicity of algal toxins.

Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties

Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties

Novel slow-binding reversible acetylcholinesterase inhibitors based on uracil moieties for possible treatment of myasthenia gravis and protection from organophosphate poisoning

A series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers were prepared and evaluated in vitro for the acetyl- and butyrylcholinesterase (AChE and BChE) inhibitory activities. These bisuracils are shown to be very effective inhibitors of AChE, inhibiting the enzyme at nano- and lower molar concentrations with extremely high selectivity for AChE vs. BChE. Kinetic analysis showed that the lead compound 2h acts as a slow-binding inhibitor of AChE and possess a long drug-target residence time (τ = 1/koff = 18.6 ± 7.5 min). Moreover, compound 2h ameliorated muscle weakness in myasthenia gravis rat model with a lower effective dose and longer lasting effect than pyridostigmine bromide. Besides, it was shown that compound 2h has an effect of increasing efficiency of antidotal therapy as a pretreatment for poisoning by organophosphates.

The First 5'-Phosphorylated 1,2,3-Triazolyl Nucleoside Analogues with Uracil and Quinazoline-2,4-Dione Moieties: A Synthesis and Antiviral Evaluation.

A series of 5′-phosphorylated (dialkyl phosphates, diaryl phosphates, phosphoramidates, H-phosphonates, phosphates) 1,2,3-triazolyl nucleoside analogues in which the 1,2,3-triazole-4-yl-β-D-ribofuranose fragment is attached via a methylene group or a butylene chain to the N-1 atom of the heterocycle moiety (uracil or quinazoline-2,4-dione) was synthesized. All compounds were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1). Antiviral assays revealed three compounds, 13b, 14b, and 17a, which showed moderate activity against influenza virus A (H1N1) with IC50 values of 17.9 μM, 51 μM, and 25 μM, respectively. In the first two compounds, the quinazoline-2,4-dione moiety is attached via a methylene or a butylene linker, respectively, to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5′-diphenyl phosphate substituent. In compound 17a, the uracil moiety is attached via the methylene unit to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5′-(phenyl methoxy-L-alaninyl)phosphate substituent. The remaining compounds appeared to be inactive against influenza virus A/PR/8/34/(H1N1). The results of molecular docking simulations indirectly confirmed the literature data that the inhibition of viral replication is carried out not by nucleoside analogues themselves, but by their 5′-triphosphate derivatives.

Intermolecular Interactions of Nucleoside Antibiotic Tunicamycin with On-Target MraYCB-TUN and Off-Target DPAGT1-TUN in the Active Sites Delineated by Quantum Mechanics/Molecular Mechanics Calculations.

Tunicamycin (TUN) is a nucleoside antibiotic with a complex structure comprising uracil, tunicamine sugar, N-acetylglucosamine (GlcNAc), and fatty acyl tail moieties. TUN, known as a canonical inhibitor, blocks vital functions of certain transmembrane protein families, for example, the insect enzyme dolichyl phosphate α-N-acetylglucosaminylphosphotransferase (DPAGT1) of Spodoptera frugiperda and the bacterial enzyme phospho-N-acetylmuramoylpentapeptide translocase (MraYCB) of Clostridium bolteae. Accurate description of protein–drug interactions has an immense impact on structure-based drug design, while the main challenge is to create proper topology and parameter entries for TUN in modeling protein–TUN interactions given the structural complexity. Starting from DPAGT1–TUN and MraYCB–TUN crystal structures, we first sketched these structural complexes on the basis of the CHARMM36 force field and optimized each of them using quantum mechanics/molecular mechanics (QM/MM) calculations. By continuing calculations on the active site (QM region) of each optimized structure, we specified the characteristics of intermolecular interactions contributing to the binding of TUN to each active site by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses at the M06-2X/6-31G** level. The results outlined that TUN insertion into each active site requires multiple weak, moderate, and strong hydrogen bonds accompanying charge–dipole, dipole–dipole, and hydrophobic interactions among different TUN moieties and adjacent residues. The water-mediated interactions also play central roles in situating the uracil and tunicamine moieties of TUN within the DPAGT1 active site as well as in preserving the uracil-binding pocket in the MraYCB active site. The TUN binds more strongly to DPAGT1 than to MraYCB. The information garnered here is valuable particularly for better understanding mode of action at the molecular level, as it is conducive to developing next generations of nucleoside antibiotics.

Synthesis, identification of some new 1,2,4-triazole derivatives from 6-amino-1,3-dimethyluracil and evaluation of their molecular docking, Anti-oxidant and experimental

The present work includes synthesis of new series of heterocyclic derivatives containing 6-amino-1,3-dimethyl uracil moiety linked to 1,2,4-triazole [6-8 and 10]. The first way includes reaction of 6-amino-1,3-dimethyluracil with ethyl chloroacetate with K2CO3 as catalyst in DMF as solvent to gives ester derivative [1]. Then, compound [1] was converted into (semicarbazide, thiosemicarbazide, phenylsemicarbazide and hydrazide derivatives) as a result of the compound [1] reaction with (semicarbazide, thiosemicarbazide, and phenylsemicarbazide and hydrazine hydrate) corresponding compound [2-5] respectively. Then, Cyclization of compound [2-5] in alkaline media (4N-NaOH) to give 1,2,4-triazole derivatives compounds [6-8] respectively. While, Compound [5] cyclization by reaction with CS2 in alkaline media (20% KOH) to give compound [9] that reacted directly with hydrazine hydrate to gives 1,3,4-triazole derivative [10]. The synthesized compounds were identified by spectral methods their [FTIR and some of them by 1HNMR, 13C-NMR] and measurements some of its physical properties and some specific testes. All the compounds were screened for in vitro antioxidant studies by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and phosphomolybdenum methods. Among the synthesized bioactive molecules [1-10] exhibited promising antioxidant activity compared with the standard drug Ascorbic acid.

Novel Slow-Binding Reversible Acetylcholinesterase Inhibitors Based on Uracil Moieties for Possible Treatment of Myasthenia Gravis and Protection from Organophosphate Poisoning

Novel Slow-Binding Reversible Acetylcholinesterase Inhibitors Based on Uracil Moieties for Possible Treatment of Myasthenia Gravis and Protection from Organophosphate Poisoning

Computational study of interactions of the uracil molecule with the F- and [formula omitted] hard anions

We report the first computational study on anion clusters of uracil with F- and O2-using the B3LYP, B3LYP-GD3 methods with the aug-cc-pVnZ basis sets, n = 2–5. In each cluster, the anion selectively abstracts a proton from a specific NH bond in uracil. The transferred proton forms an incipient chemical bond with the anion while the transferred proton becomes hydrogen bonded to the uracil moiety. Most of the anion’s negative charge is transferred to uracil while the electron-spin density is redistributed among the oxygen atoms in O2-. We identified two pathways for dissociation and vibrationally induced proton transfer within each complex. There are large red shifts in frequencies and massive increase in intensities of the IR stretches in the protonated anions within the clusters. These new findings advance our knowledge about interactions of O2-with nucleotide bases and provide predictions for IR spectroscopic detection of the O2- uracil cluster.

Treatment of cylindrospermopsin by hydroxyl and sulfate radicals: Does degradation equal detoxification?

Drinking water treatment ultimately aims to provide safe and harmless drinking water. Therefore, the suitability of a treatment process should not only be assessed based on reducing the concentration os a pollutant concentration but, more importantly, on reducing its toxicity. Hence, the main objective of this study was to answer whether the degradation of a highly toxic compound of global concern for drinking water equals its detoxification. We, therefore, investigated the treatment of cylindrospermopsin (CYN) by •OH and SO4-• produced in Fenton and Fenton-like reactions. Although SO4-• radicals removed the toxin more effectively, both radical species substantially degraded CYN. The underlying degradation mechanisms were similar for both radical species and involved hydroxylation, dehydrogenation, decarboxylation, sulfate group removal, ring cleavage, and further fragmentation. The hydroxymethyl uracil and tricyclic guanidine moieties were the primary targets. Furthermore, the residual toxicity, assessed by a 3-dimensional human in vitro liver model, was substantially reduced during the treatment by both radical species. Although the results indicated that some of the formed degradation products might still be toxic, the overall reduction of the toxicity together with the proposed degradation pathways allowed us to conclude: “Yes, degradation of CYN equals its detoxification!”.

X-ray induced luminescence spectroscopy for DNA damaging intermediates aided by a monochromatic synchrotron radiation

Purpose To identify the bonding sites of initial radiation interaction with DNA and to trace the following chemical reaction sequences on the pathway of damage induction, we carry out a spectroscopy XIL (X-ray induced luminescence) using soft X-ray synchrotron radiation. This is a nondestructive analysis of the excited intermediate species produced in a molecular mechanism on the damage induction pathway. Materials and Methods We introduce aqueous samples of UMP (uridine-5’-monophosphate) in the vacuum by the use of a liquid micro-jet technique. The luminescence in the region of UV-VIS (from visible to ultraviolet) radiation induced after the absorption of monochromatic soft X-ray by aqueous UMP is measured with sweeping the soft X-ray energy in the region of 370–560 eV. Results The enhanced XIL intensities for aqueous UMP in the region of soft X-ray of 410–530 eV (in “water window” region) are obtained. The enhancement of XIL intensities in the UV-VIS region, relative to the water control, is explained by the excitation and ionization of a K-shell electron of nitrogen atoms in the uracil moiety. The enhanced XIL intensities do not match the structure of XANES (X-ray absorption near-edge structure) of the aqueous UMP. This suggests that the XIL intensities reflect the quantum yields of luminescence, or the quantum yields for conversion by UMP of an absorbed X-ray into UV-VIS radiation. In this paper, spectra of luminescence are shown to be resolved by combining low pass filters. The filtered luminescence spectra are obtained at the center of gravity (λc) of the band pass wavelength regions at λc = 270nm, 295 nm, 340 nm, 385 nm, 450 nm, and 525 nm., which show a trend similar to the fluorescence of nucleobases induced by ultraviolet radiation. Conclusion It is concluded that the origin of the observed XIL is the hydrated uracil moiety in aqueous UMP, decomposition of which is suppressed by the migration of excess charge and internal energy after the double ionization due to Auger decay.

Mercury-containing supramolecular micelles with highly sensitive pH-responsiveness for selective cancer therapy

Construction and manipulation of metal-based supramolecular polymers—which are based on a combination of nucleobase hydrogen bonding interactions and functional metal ions—to obtain the desired physicochemical properties and achieve the efficacy and safety required for biomedical applications remain extremely challenging. We successfully designed and synthesized a new mercury-based supramolecular polymer, Hg-BU-PPG, containing an oligomeric polypropylene glycol backbone and pH-sensitive uracil-mercury-uracil (U-Hg-U) linkages. This multifunctional metallo-supramolecular material spontaneously self-organizes into nanosized spherical micelles in aqueous solution. The micelles possess several attractive properties, including desired long-term structural stability in serum-rich conditions, unique fluorescence behavior and highly sensitive, well-controlled pH-responsiveness. Interestingly, Hg-BU-PPG micelles exhibited strong, selective cytotoxic effects towards cancer cells in vitro, without harming normal cells. The highly selective cytotoxicity can be attributed to rapid dissociation of the U-Hg-U complexes within the micelles in the mildly acidic intracellular pH of cancer cells, followed by release of inherently toxic mercury ions. Importantly, fluorescence microscopy and flow cytometry clearly demonstrated that Hg-BU-PPG selectively entered the cancer cells via endocytosis and rapidly promoted massive apoptotic cell death. In contrast, internalization of Hg-BU-PPG by normal cells was limited, resulting in high biocompatibility and no cytotoxic effects. Thus, this newly discovered ‘cytotoxicity-concealing’ supramolecular system could represent a viable route to enhance the safety and efficacy of cancer therapy and bioimaging via a strategy that does not require incorporation of anticancer drugs and fluorescent probes. Statement of significanceWe report a significant breakthrough in the construction of mercury-containing supramolecular polymers, namely the creation of multifunctional micelles with unique chemical and physical properties conferred by pH-sensitive uracil-mercury-uracil (U-Hg-U) linkages and tunable structural and dynamical features due to the presence of hydrogen-bonded uracil moieties. Importantly, in vitro experiments clearly demonstrated that introduction of the U-Hg-U complexes into the micelles not only improved the efficiency of selective uptake via endocytosis into cancer cells, but also accelerated the induction of massive apoptotic cell death. Thus, this work provides crucial new insight for the development of metallo-supramolecular polymeric micelles that may substantially enhance the safety and efficacy of cancer therapy and bioimaging without requiring incorporation of anticancer drugs or fluorescent probes.

Advances in the Synthesis of Marine‐sourced Natural Product via the Preparation of Pyrimidinyl Benzamides by Amide Bond Formation

Efficient, scalable total synthesis of 4-Amino-N-(2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl) benzamide, a marine-sourced compound with antibacterial properties is introduced, highlighting the importance of nature and its selection process to produce effective antibacterial compounds, thus serving as a template in the development of new drugs. We proposed a one-pot process where 6-aminouracil was acylated using 4-N-Boc-aminobenzoyl chloride over an expansive range of solvents and temperatures. We also proposed a one-pot carbodiimide mediated carboxylic acid coupling with 6-aminouracil. Both processes were unsuccessful and the difficulty encountered in these approaches is likely due to the reduced nucleophilicity of the amino group of 6-aminouracil. Literature studies helped refocus our approach to exploit the pyrimidine character of the uracil as a workaround, employing a dialkoxy aminopyrimidine, which is a precursor to our specific uracil starting material. The 4-amino-2,6-dimethoxypyrimidine was extensively screened for the same two reactions using a variety of solvents and temperatures, with the key amide bond successfully being formed using benzoyl chloride in excess pyridine. The amide bond formation was further optimized, obtaining a purer, higher-yielding coupling product. Current work involves dealkylation of the pyrimidine to furnish the uracil moiety as the final step in a three-step total synthesis. The attempted acidic demethylation of a methoxypyrimidine substrate resulted in undesired amide bond cleavage. Future work involves attempting the demethylation of the methoxypyrimidine substrate using a variety of Lewis acids and if successful, testing the natural product's antibiotic properties. The pyrimidinyl benzamides themselves may have useful biological activities which would be worth investigating as well.

Deciphering the Chemical Basis of Fluorescence of a Selenium-Labeled Uracil Probe when Bound at the Bacterial Ribosomal A-Site.

We unveil in this work the main factors that govern the turn-on/off fluorescence of a Se-modified uracil probe at the ribosomal RNA A-site. Whereas the constraint into an "in-plane" conformation of the two rings of the fluorophore is the main driver for the observed turn-on fluorescence emission in the presence of the antibiotic paromomycin, the electrostatics of the environment plays a minor role during the emission process. Our computational strategy clearly indicates that, in the absence of paromomycin, the probe prefers conformations that show a dark S1 electronic state with participation of nπ* electronic transition contributions between the selenium atom and the π-system of the uracil moiety.

Aminocatalytic Synthesis of Uracil Derivatives Bearing a Bicyclo[2.2.2]octane Scaffold via a Doubly Cycloadditive Reaction Cascade

AbstractAminocatalytic synthesis of highly enantiomerically enriched uracil derivatives bearing a bicyclo[2.2.2]octane scaffold is described. The developed strategy utilizes 1,3,6-trimethyl-5-formyluracil and α,β-unsaturated aldehydes as starting materials and has been realized employing various aminocatalytic activation strategies operating in a synergistic manner. The reaction cascade can be described as doubly cycloadditive as it consists of two consecutive Diels–Alder cycloadditions allowing for a facile construction of the bicyclo[2.2.2]octane scaffold. Notably, both steps proceed with dearomatization of the partially aromatic uracil moiety. Excellent stereoselectivity of the reaction cascade is ensured by the use of 2-(diphenylmethyl)pyrrolidine as aminocatalyst.

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease.

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.

New acetamide derivatives containing (ω-p-bromophenoxyalkyl)uracil moiety and their anticytomegalovirus activity

New N-aryl-2-{3-[ω-(4-bromophenoxy)alkyl]-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl}acetamides have been obtained from 1-[ω-(4-bromophenoxy)alkyl]uracil and 2-chloro-N-(4-phenoxyphenyl)acetamide derivatives. Investigation of their antiviral properties against human cytomegalovirus revealed that the representative with dodecane-1,12-diyl linker exhibited powerful virus inhibitory activity in vitro.

Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides.

Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2′,3′,5′-tri-O-benzoyl-d-ribofuranose and 5-substituted uracil moieties and have half-maximal inhibitory concentrations (IC50) in the lower micromolar and submicromolar range. 2′,3′,5′-Tri-O-benzoyl-5-iodouridine manifested the strongest inhibitory effect on Tdp1 (IC50 = 0.6 μM). A decrease in the number of benzoic acid residues led to a marked decline in the inhibitory activity, and pyrimidine nucleosides lacking lipophilic groups (uridine, 5-fluorouridine, 5-chlorouridine, 5-bromouridine, 5-iodouridine, and ribothymidine) did not cause noticeable inhibition of Tdp1 (IC50 > 50 μM). No PARP1/2 inhibitors were found among the studied compounds (residual activity in the presence of 1 mM substances was 50–100%). Several O-benzoylated uridine and cytidine derivatives strengthened the action of topotecan on HeLa cervical cancer cells.