Pyrimidine Ring Research Articles

Cross-linked ultrathin polyphosphazene-based nanosheet with promoted charge separation kinetics for efficient visible light photocatalytic CO2 reforming to CH4

Organic polymer materials as a promising type of photocatalyst are still limited by the poor transport efficiency of photoinduced carrier. Herein, a series of cross-linked ultrathin polyphosphazene-based nanosheets is developed by regulating the N-containing skeleton. The aromatic ring, pyrimidine ring and s-triazine ring are bonded with cyclotriphosphazene to form large-sized 2D nanosheets, respectively. Experimental results and theoretical calculations have determined the pyrimidine ring that has a stronger ability to adsorb CO2 and can provide a suitable band gap and a stronger built-in electric field, so as to realize the rapid separation of photoproduced carrier. 2PC sample with the pyrimidine ring delivered near 100% selectivity for CO2-to-CH4 conversion with an impressive rate of 626 µmol g−1 without cocatalyst and photosensitizer under visible light illumination, surpassing many reported photocatalysts. Briefly, this work offers a fresh means for the construction of high-performance polymers by regulating the internal framework.

Synthesis of Novel Diastereomer Pyrimido[1,2-a]Benzimidazoles by Using Silica Sulfuric Acid/Ethylene Glycol

The scope of the reaction of 2-aminobenzimidazole, aldehydes and diethyl malonate in the presence of silica sulfuric acid/ethylene glycol was investigated. The reaction gave two unexpected products, 2-hydroxyethyl 3-hydroxy-4-aryl-2-oxo-tetrahydropyrimidobenzimidazole-3-carboxylates 2 and 4-aryl-hydropyrimido[1,2-a]- benzimidazol-2(1H)-ones 3 without isolation of the expected ethyl 4-aryl-2-oxo-1,2,3,4-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-3-carboxylates 1. NMR spectroscopic data and X-Ray analysis were used for assignment and confirmation the structures of the unexpected products. 2-Hydroxyethyl carboxylate derivatives 2 may be obtained via formation of 1 as intermediates, which were subjected to trans-esterification by ethylene glycol and oxidation of the proton on pyrimidine ring at position-3 to afford products 2. The unexpected products 3 may be obtained via formation of compounds 1 that was subjected to deesterification followed by decarboxylation to afford compounds 3.

Synthesis, biological evaluation and induced fit docking simulation study ofd-glucose-conjugated 1H-1,2,3-triazoles having 4H-pyrano[2,3-d]pyrimidine ring as potential agents against bacteria and fungi

Gluco-conjugated 1H-1,2,3-triazoles having 4H-pyrano[2,3-d]pyrimidines are synthesized via click chemistry of N-propargyl-4H-pyrano[2,3-d]pyrimidines and glucopyaranosyl azide using CuI@Montmorillonite. Their antibacterial, anti-MRSA, and antifungal activity is probed.

Study of Antiviral Activity of Some Pyrimidine Ring Containing Compounds against COVID-19 Based on Molecular Docking and Quantum Chemical Calculations by DFT Method

The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic and currently no specific drug is available to prevent or cure this novel coronavirus (SARS-CoV-2) disease. We have been put forth five pyrimidine ring containing compounds as potential antiviral candidatures for the treatment of COVID-19 diseases based on quantum chemical properties predicted by molecular docking study and DFT calculations at the level of B3LYP method with 6-311++G (d,p) basis set. Our findings were also compared to remdesivir, a control ligand. Blind docking with the main protease revealed that the ligands preferentially bind to the active site. Interestingly, all of the ligands exhibited low binding free energies i.e., strong inhibitory interactions with the active sites of the main protease. Ligand L1 was one of them, which revealed significantly low binding energies (-8.8 kcal/mol) with SARS-CoV-2 Mpro. These binding energies are even lower than those of remdesivir’s potent active metabolite. All of the drugs interact with the key active site residues, including His41 and Cys145. These findings are also strongly supported by quantum chemical investigations.

Heterocyclic compounds containing thiazole ring as important material in medicinal chemistry

Thiazoles are among the most important heterocyclic compounds that contain sulphur at positions 1 and nitrogen at positions 3 in a 5-membered ring. Thiazoles possess an excellent biological activity because of the presence of N and S atoms. These heteroatoms play an important role in the coordination chemistry and bind at active sites of the metal ions which increase their therapeutic activity. Many natural products possess the thiazole ring structure, which has sulphur and nitrogen heteroatoms. Thiamine (vitamin B1) is the most important naturally occurring thiazole derivative in which both pyrimidine and thiazole rings are present. In the present research work, derivatives of 2‐amino thiazol have been synthesized. These ligands were further reacted with Cu salts to synthesise metal complexes. Many of the researchers are interested in the thiazole derivatives and their complexes because of their application as good biological active compounds in antibacterial, antifungal, and antioxidant activity.

Design, Synthesis and Evaluation of Novel Thiopyrimidine-Glucuronide Compounds with Promising Biological Activities

3-Methyl-5-acetyl-7-[(2-sulfanylidene-6-aryl-1,2-dihydropyrimidin-4-yl)amino]-1,2-benzisoxazoles (2a-n) were obtained from N-(5-acetyl-3-methyl-1,2-benzoxazol-7-yl)-3-arylprop-2-enamides (1a-n) and thiourea. Products (2a-n) oxidized with KMnO4 to afford 5-acetyl-7-[(2-sulfanylidene-6-aryl-1,2- dihydropyrimidin-4-yl)amino]-1,2-benzisoxazole-3-carboxylic acids (3a-n). Reaction of 3a-n with D-gluconic acid and pyridine yielded β-D-glucuronosyl-5-acetyl-7-[(2-sulfanylidene-6-aryl-1,2- dihydropyrimidin-4-yl)amino]-1,2-benzisoxazol-3-carboxylates (4a-n). The present synthesis featured the formation of dihydropyrimidine skeleton through ring closure of key intermediates and installation of pyrimidine ring with amino group. The structures of all the newly synthesized compounds were characterized by analytical data, IR, 1 H NMR and mass spectrometry.

A bifunctional chemical signature enabling RNA 4-thiouridine enrichment sequencing with single-base resolution.

Both sequence enrichment and base resolution are essential for accurate sequencing analysis of low-abundance RNA. Yet they are hindered by the lack of molecular tools. Here we report a bifunctional chemical signature for RNA 4-thiouridine (4sU) enrichment sequencing with single-base resolution. This chemical signature is designed for specific 4sU labeling with two functional parts. One part is a distal alkynyl group for the biotin-assisted pulldown enrichment of target molecules via click chemistry crosslinking. The other part is a -NH group proximal to the pyrimidine ring of 4sU. It allows 4sU-to-cytosine transition during the polymerase-catalyzed extension reaction based on altering hydrogen-bonding patterns. Ultimately, the 4sU-containing RNA molecules can be enriched and accurately analyzed by single-base resolution sequencing. The proposed method also holds great potential to investigate transcriptome dynamics integrated with high-throughput sequencing.

Design, Synthesis, and Biological Activity Evaluation of Novel Tubulin Polymerization Inhibitors Based on Pyrimidine Ring Skeletons

Design, Synthesis, and Biological Activity Evaluation of Novel Tubulin Polymerization Inhibitors Based on Pyrimidine Ring Skeletons

Synthesis of 2,7-diarylpyrazolo [1,5-a] pyrimidine derivatives with antitumor activity. Theoretical identification of targets

The pyrazolo[1,5-a]pyrimidine ring system constitutes a privileged scaffold for developing drug-like compounds, whose biologic activity is dictated by the nature and position of the substituents on the heterocyclic core. Herein, we report the synthesis of nine 2,7-diarylpyrazolo[1,5-a]pyrimidine derivatives and the assessment of their antitumor activity against a colorectal carcinoma cell line. Four compounds showed substantially impaired cell viabilities. We carried out a virtual reverse screening campaign to identify their biological targets. The results showed that many putative targets had been related to cancer, particularly colorectal carcinoma, which supports the computational strategy. The structural and physicochemical information available for the complexes between active compounds and identified targets offers the opportunity to design new derivatives, which optimize interactions and improve the binding energy.

Study of the alkyl-π interaction between methane and few substituted pyrimidine systems using DFT, AIM and NBO calculations

In the present study alkyl-π interactions between methane and the pyrimidine heterocyclic systems have been studied. Interaction energies were calculated using the B97D/def2-TZVPP level of theory. Energy decomposition analysis (EDA) using SAPT0/ jun-cc-pVTZ method revealed that the interaction energy is mainly dispersion and electrostatic with a minor contribution from induction energy. Non covalent index analysis was performed to visualize the interactions between the fragments of the studied complexes and atoms in molecule (AIM) study were done to investigate the bond critical points (BCP). The natural bond order (NBO) analyses were carried out to study the donor-acceptor orbitals and the second-order perturbation energies. Interaction energy, AIM study and NBO analysis revealed that the alkyl-π interactions involving the pyrimidine heterocyclic systems become stronger with the presence of various substituents on the pyrimidine ring.

Synthesis and Investigation of Thermal, Optical and Electrochemical Properties of 2,4,6‐Trisubstituted Pyrimidines

AbstractA number of novel fluorophores have been synthesized containing an electron‐withdrawing pyrimidine core and electron donating N,N‐dimethylaminophenyl, 4‐(9H‐carbazol‐9‐yl)phenyl, phenyl and pyrrol‐1‐yl fragments at positions 2, 4 and 6 of the pyrimidine ring. Thermal, optical and electrochemical properties of these substances have been studied. The structure‐property dependences of substituted pyrimidines have been established.

Synthesis, X-ray crystallographic analysis, DFT studies and biological evaluation of triazolopyrimidines and 2-anilinopyrimidines

Inspired by the reported antiviral activity of pyrimidines and triazolopyrimidines, two series of 2-anilinopyrimidines (5a-e) and 1-aryl-[1,2,4]triazolo[4,3-a]pyrimidines (14a-k) were designed and synthesized as potential antiviral agents. X-ray crystallographic study of compounds (14d) and (14k) confirmed the structure of the desired isomer and revealed the coplanarity of the fused [1,2,4]triazolo[4,3-a]pyrimidine rings with the aryl side group. DFT studies revealed insights into the mechanism of the micro-reversible cyclisation step using DFT [B3LYP-D3(BJ)/6–31++G(d,p)]. The pharmacokinetic properties and calculation of drug likeness scores (DLS) of (5a-e) and (14a-k) suggested good traditional drug-like properties and led to the synthesis of derivatives (14a-k) which were evaluated for their anti-viral activity with the most potent derivatives subjected to cytotoxicity screening. Compounds (14a), (14c), (14e), (14f) and (14k) showed moderate to strong antiviral activity with EC50 values 38 - 186 μM. Compound (14e) (DLS = 0.29) showed the best anti-CHIKV activity (EC50 = 38 μM) and lowest cytotoxicity (CC50 > 300 μg/ml) against breast cancer cell lines, MCF-7 and MD-AMB-231 and normal cell line EA.hy926. Simplification of [1,2,4]triazolo[4,3-a]pyrimidine ring, led to series (5a-e) (DLS = 0.03 - 0.77). Derivatives (5a-d) showed fair anti-CHIKV activity (EC50 > 200 μM), while (5e) emerged as the most active antiviral agent, however the most cytotoxic.

Multicomponent Approach for the Sustainable Syntheses of Pyrido[2,3-d]pyrimidine Scaffold

Pyrido[2,3-d]pyrimidine is an N-fused heterocyclic compound formed by the ortho fusion of pyridine and pyrimidine ring. Pyrido[2,3-d]pyrimidines hold a prominent position in medicinal chemistry owing to their wide spectrum of biological activities like antiviral, antihistaminic, antibacterial, diuretic, anti-inflammatory, analgesic, anticonvulsive, antipyretic, etc. The extraordinary features of pyrido[2,3-d]pyrimidines make their synthesis a perpetual field of research. Moreover, the construction of elaborate biologically relevant moieties via a multicomponent approach has become a promising area of research, owing to the burgeoning ‘green chemistry drive’. Advances in the exploitation of proficient synthetic routes involving a multicomponent approach for the assembly of this scaffold are reported in this review.

Synthesis, Anti-Tomato Spotted Wilt Virus Activities, and Interaction Mechanisms of Novel Dithioacetal Derivatives Containing a 4(3H)-Quinazolinone Pyrimidine Ring.

A series of unreported novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring were synthesized, and their antiviral activities were evaluated against tomato spotted wilt virus (TSWV). A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was established, and compound D32 was designed and synthesized according to the analysis results of the CoMFA and CoMSIA models. The bioassay results showed that compound D32 exhibited excellent inactivation activity against TSWV, with EC50 values of 144 μg/mL, which was better than those of ningnanmycin (149 μg/mL) and the lead compound xiangcaoliusuobingmi (525 μg/mL). The binding ability of compound D32 to TSWV CP was tested by microscale thermophoresis (MST), and the binding constant value was 4.4 μM, which was better than those of ningnanmycin (6.2 μM) and xiangcaoliusuobingmi (59.1 μM). Therefore, this study indicates that novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring may be applied as new antiviral agents.

Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies

Molecular hybridization (MH) of heterocyclic rings has enabled scientists to design and develop novel drugs and drug-like candidates. In our previous work, considering the importance of MH, we synthesized different kinds of chloropyrazine-tethered pyrimidine derivatives (22–40) containing either substituted phenyl or heteroaryl rings at position-6 of the pyrimidine ring and evaluated their antitubercular activity. Herein, we report the antimicrobial and antiproliferative activities of 22–40. The antiproliferative activity of the target hybrids was superior to the antimicrobial activity. However, some compounds showed greater antimicrobial activity than the standard drugs. For instance, among the nineteen derivatives, compound 31 containing a 2″,4″-dichlorophenyl ring, showed the most potent antibacterial and antifungal activities (MIC 45.37 µM), followed by compounds 25 and 30 bearing 4″-nitrophenyl and 2″,4″-difluorophenyl scaffolds with minimum inhibitory concentrations (MIC) values of 48.67 µM and 50.04 µM, respectively. Compound 35, containing a bioisosteric 2″-pyridinyl ring, showed the most potent antiproliferative activity against the prostate cancer cell line (DU-145) with an IC50 value of 5 ± 1 µg/mL. Additional testing of compounds 22–40 on human normal liver cells (LO2) indicated that the compounds were more selective to cancer cell lines over normal cells. Further, molecular docking of the most potent compound 35 against dihydrofolate reductase (DHFR) (PDB ID: 1U72) had a good binding affinity with a docking score of −6.834. The SwissADME program estimated the drug-likeness properties of compound 35. Hybrid 35 is a potential lead molecule for the development of new anticancer drugs, whereas 31 is a promising antimicrobial lead candidate.

Mechanistic studies of dinucleotide and oligonucleotide model cyclobutane pyrimidine dimer (CPD) DNA lesions under alkaline conditions

Cyclobutane pyrimidine dimers (CPDs) are the most abundant mutagenic DNA lesions formed in mammalian cells upon exposure to UV-B radiation (280–315 nm) in sunlight. These lesions are thought to be chemically stable and to withstand high concentrations of acids and bases.While earlier investigations of DNA lesions containing saturated pyrimidines have shown that the C4 carbonyl is a potential target of nucleophilic attack, similar reactions with thymine nucleobase model CPDs clearly showed that the cis-syn CPD (major isomer) is stable in the presence of a high concentration of alkali at room temperature. Here is described the alkaline reactivity of these lesions when contained within a dinucleotide CPD model system. Results using cis-syn CPD formed from dinucleotide 5′-TpT-3′ combined with [18O]-labelling indicated that CPD undergoes a water addition at the C4=O groups of these now saturated rings. The intermediate formed, however, completely reverts to the starting lesion. Along with confirming the target of water addition within CPD lesions, it was also determined that the two C4 carbonyls present on adjacent saturated pyrimidine rings of the photolesion undergo water exchange at different rates (3′ > 5′). Moreover, the difference in reactivity exhibited by these two positions is not limited to a dinucleotide and was observed also in oligonucleotides. Overall, a full understanding of the chemistry of CPD lesions is crucial to our knowledge of naturally-occuring DNA modifications and may lead to further insight into their detection, modification, and biochemical recognition & repair.

Investigating thiouracil adsorption by an iron-doped carbon particle: Analyzing structural, electronic, and QTAIM features

This work was performed to examine thiouracil (TU) adsorption by an iron-doped metal carbon particle (MCP) for providing information towards drug delivery purposes. To this aim, four types of TU related compounds were investigated including the parent uracil (U), 2,4-dithiouracil (TU), 2-thiouracil (2TU), and 4-thiouracil (4TU). The MCP model was created by substitution of one iron (Fe) atom instead of one carbon atom of a C20 fullerene-like cage resulting C19Fe model. TU models were relaxed at the Fe region of MCP by considering the separated relaxation processes for each of urea-type and amide-type atoms of pyrimidine ring. Density functional theory (DFT) computations were performed to obtain the optimized structures in addition to evaluation of other related features. The stabilized models indicated that the role of urea-type S atom was significant for formation of strong complexes with the MCP. Various types of energies, molecular orbital features, natural bond orbital (NBO) atomic charges, and quadrupole coupling constants were used for analyzing the models. Furthermore, the quantum theory of atoms in molecules (QTAIM) approach was employed to recognize the strength of interactions of TU@MCP complex models. As a final remark, the obtained results demonstrated the promising role of MCP as a conducting carrier towards drug delivery of TU.

Facile synthesis of superparamagnetic thiamine/Fe3O4 with enhanced adsorptivity toward divalent copper ions

The development of environmentally friendly adsorbents has been extensively carried out to overcome the detrimental effects of heavy metal accumulation, which has persistently become a global ecological problem. In pursuit of generating eco-friendly adsorbents, a green method for synthesizing thiamine functionalized-Fe3O4 (FT) was developed in this study. A one-step chemical oxidation and functionalization technique was used to prepare FT using the ammonia-containing solvent. A molar ratio of ammonia:Fe:thiamine of 15:1:1 was shown to produce FT15 with high yield, adsorptivity, and purity. XRD, XPS, FTIR, SEM, and SQUID characterization of FT15 revealed the formation of superparamagnetic thiamine functionalized Fe3O4 in their particles. This superparamagneticity facilitates the easy recovery of FT15 particles from the waste-containing solution by using an external magnetic force. The batch adsorption of Cu(II) onto FT15 showed the best fit with the Sips adsorption isotherm model with a maximum adsorption capacity of 426.076 mg g−1, which is 5.69-fold higher capacity than the control unmodified Fe3O4 (F15). After five adsorption-desorption cycles, the FT15 can maintain up to 1.95-fold higher capacity than the freshly synthesized F15. Observation on the physicochemical properties of the post-adsorption materials showed the contribution of an amine group, pyrimidine ring, and the thiazolium group of thiamine in boosting its adsorption capacity. This study provides important findings to advance the adsorptivity of magnetic adsorbents with promising recoverability from aqueous solution by employing naturally available and environmentally friendly compounds such as thiamine.

Design synthesis and photophysical properties of a novel antitumor fluorescence agents

• Four fluorescent compounds with boron fluoride groups were synthesized. • Cytotoxicity analysis: compound L4 had an IC50 value of 19.24 ± 5.88 in Hera cells. • Flow cytometry analysis: compound L4 induced early apoptosis of Hera cells accounted for 31.3%. • The result of molecular docking show that hydrogen bond, π-π bonding and T-π bonding are the main forces. Four novel fluorescent antitumor compounds were synthesized in three steps. In this paper, boron fluoride was introduced into the side bond of pyrimidine ring through a simple synthetic route, which enhanced the fluorescence intensity and anti-tumor activity. Through MTT test, the IC 50 values of the four compounds reached the expected effect. Compound L4, in particular, had an IC 50 value of 19.24 ± 5.88 in HeLa cells, which was slightly higher than that of 5-fluorouracil. Flow cytometry analysis showed that the four compounds had the ability to induce apoptosis of tumor cells, and compound L4 induced early apoptosis of Hela cells accounted for 31.3%. At the same time, molecular docking were carried out of four compounds by Molecular operating environment (MOE) software package version AutoDock Vina 1.1.2. The results show that hydrogen bond, π-π bonding and T-π bonding are the main forces. This provides a new idea for tumor therapy and potential for rapid identification of drug concentration in cells.

Inhibition mechanisms of humic acid and protein on the degradation of sulfamethazine by horseradish peroxidase

Humic acid and protein are not only common organic matters in surface water, but also the main components of the extracellular polymer of microorganisms, which can influence on the biotransformation and biodegradation of antibiotics by enzymes. Therefore, the influence of fulvic acid and protein on the biotransformation of sulfamethazine (SMR) by horseradish peroxidase (HRP) was explored. HPLC-MS analysis show that 79.7% of SMR (20 mg/L) was degraded by sulfa bond breaking, hydroxyl substitution and pyrimidine ring opening, while the removal rate was suppressed significantly in the presence of fulvic acid or bovine serum albumin (BSA, model protein). This inhibition is related to the concentration of fulvic acid or BSA, but not to the exposure time. The inhibition of fulvic acid on SMR degradation by HRP is mainly achieved by binding to the HRP-SMR intermediate to prevent the HRP-SMR intermediate from further generating HRP and products, which is called anticompetitive inhibition. HRP activity is not affected by the addition of BSA with time. The inhibition of BSA on SMR degradation by HRP may be achieved by competing with HRP for binding to SMR, which is confirmed with the analysis of molecular docking. • Fulvic acid or protein (BSA) inhibits the degradation of sulfamethazine by HRP. • The inhibition is related to the concentration of fulvic acid or BSA but not to time. • Competitive inhibition of protein on the degradation of sulfamethazine by HRP. • Anticompetitive inhibition of humic acid on the degradation of sulfamethazine by HRP.