Pyrimidine Ring Research Articles

Role of Pyrimidine Derivatives in the Treatment of Cancer

The study of the chemistry of pyrimidines is contributing to the expansion of research into the therapeutic applications of these compounds. In the field of medicinal chemistry, the sheer number of pyrimidine synthesis methods and reactions that are available opens up a world of possibilities. These investigations have been inspired by the fact that pyrimidines can be used as building blocks for a wide variety of compounds that have a physiological effect. The pyrimidine ring and its fused derivatives, which include pyrazolo[3,4-d]pyrimidine, pyrido[2,3-d]pyrimidine, quinazoline, and furo[2,3-d]pyrimidine, have garnered a great deal of attention due to the extensive variety of biological potential that they possess. In addition, fused pyrimidines are considered to be bioisosteres with purines. As a consequence of this, numerous substances, such as pyrimidine and derivatives of fused pyrimidine, have demonstrated promising anticancer potential. Pyrimidine compounds have been shown to possess a number of beneficial qualities, including antibacterial, anticancer, anti-inflammatory, antidiabetic, and analgesic effects. The purpose of this study is to shed light on the anticancer significance of certain fused pyrimidine derivatives and privileged pyrimidines through the use of various types of inhibition. Additionally, the study reveals structure-activity relationships and provides specifics regarding the synthetic compounds that were utilized in the construction of these scaffolds. The hope is that this research will assist medicinal chemists in the development of highly selective pyrimidine anticancer agents. The focus of this review article is on recent research on synthetic pyrimidine compounds that have anticancer effects. Additionally, the paper examines the chemistry and biological activities of pyrimidines.

Quinoline- and pyrimidine-based allosteric modulators of the sarco/endoplasmic reticulum calcium ATPase.

Small-molecule allosteric activators of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA) hold promise as novel experimental tools to manipulate intracellular calcium concentrations and as therapeutic agents to treat medical conditions associated with elevated cytosolic calcium levels. Here, we synthesized and characterized 20 analogs of the known allosteric SERCA activator CDN1163 and tested their ability to stimulate SERCA activity. The structures of the compounds varied in the alkyl group of the parent scaffold's ether moiety as well as in the composition of the nitrogenous aromatic ring system. The most active compounds exhibited potencies in the sub-micromolar range while increasing enzyme activity by more than 25%. The observed structure-activity relationships indicated that bulky alkyl groups in the ether moiety along with a quinoline ring methyl substituent were beneficial for activity. Replacement of the quinoline by a pyrimidine ring system reduced activity. To conceive a potential mechanism of action, we generated a molecular model of the transition state of SERCA when undergoing the rate-limiting step of its catalytic cycle. Subsequent blind docking with CDN1163 identified a high-affinity binding site close to the enzyme's ATP binding pocket, suggesting that the activators may accelerate SERCA's catalytic cycle by aiding in ATP binding and positioning.

Enhanced bioremediation of bensulfuron-methyl contaminated soil by Hansschlegelia zhihuaiae S113: metabolic pathways and bacterial community structure

Bensulfuron-methyl (BSM), a widely used herbicide, can persist in soil and damag sensitive crops. Microbial degradation, supplemented with exogenous additives, provides an effective strategy to enhance BSM breakdown. Hansschlegelia zhihuaiae S113 has been shown to efficiently degrade this sulfonylurea herbicide. However, depending solely on a single strain for degradation proves inefficient and unlikely to achieve ideal remediation in practical applications. This study assessed the impact of various carbon sources on the degradation efficiency of S113 in BSM-polluted soil. Among these, glucose was the most effective, achieving a 98.7% degradation rate after 9 d of inoculation. In addition, seven intermediates were detected during BSM degradation in soil through the cleavage of the phenyl ring ester bond, the pyrimidine rings, and urea bridge peptide bond, among other pathways. 2-amino-4,6-dimethoxy pyrimidine (ADMP), and 2-(aminosulfonylmethyl)-methyl benzoate(MSMB) were the primary intermediates. These metabolites were less toxic to maize, sorghum, and bacteria than the BSM. Community structure analysis indicated that variations in exogenous carbon sources and environmental pollutants significantly improved the ecological functions of soil microbial communities, enhancing pollutant degradation. Addition of carbon sources notably affected soil microbial community structure, modifying metabolic activities and interaction patterns. Specifically, glucose substantially increased the richness and diversity of soil bacterial communities. These findings offer valuable insights for field remediation practices and contributed to the development of more robuste soil pollution management strategies.

Synthesis, highly potent α-glucosidase inhibition, antioxidant and molecular docking of various novel dihydropyrimidine derivatives to treat diabetes mellitus

1,4-dihydropyrimidine-2-thiones were synthesized in five series that include 5-carboxylic acid derivatives of dihydropyrimidine (series A, 6–8), novel 5-carboxamide derivatives of dihydropyrimidine (series B, 9–14), N,S-dimethyl-dihydropyrimidine (series C, 15–20), N-hydrazinyl derivatives of dihydropyrimidine (series D, 21–24) and tetrazolo dihydropyrimidine derivatives (series E, 25–28), and evaluated for anti-diabetic capability. The prepared novel compounds were structurally established by FTIR, 1HNMR, 13CNMR, ESI and HRMS. All of these compounds from series A-E were first time examined for α-glucosidase inhibition as to evaluate their anti-diabetic potential. Most of the compounds for example 8, 11–14, 15, 17–21, 25 and 28 demonstrated greater α-glucosidase inhibitory effects (IC50 = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC50 = 52.02 ± 0.36 μM). Compounds from series B and C found to be highly active however, the compounds from series D found generally less active. The structure–activity relationships demonstrated the importance of C-5 carboxamides, C-5 ethyl ester functionality, and the presence of N,S-dimethyl groups at pyrimidine ring for α-glucosidase inhibition. The docking studies demonstrated that all the active compounds have van der Waal and alkyl bonds interactions with the targeted site of the human lysosomal acid α −glucosidase. All these compounds were also tested for antioxidant potential by DPPH radical scavenging protocol that exhibited significant antioxidant effects (IC50 = 21.4 ± 0.45 to 92.1 ± 0.38 μM) as compared to the standard butylated hydroxyanisol (IC50 = 44.2 ± 0.36 μM). Among all, compound 13, 14 and 19 with potent α-glucosidase inhibition (IC50 = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC50 = 21.4 ± 0.45 to 31.2 ± 0.23 μM) indicated their ability to use as valuable leads for the development of anti-diabetic drugs with the combined effects of antioxidants.

Benchmarking luminescent properties of the arylvinylpyrimidine scaffold.

The exploration of the photophysical properties of push-pull molecules incorporating pyrimidine rings as electron-attracting moieties in their structure continues to be a fascinating area of investigation. A thorough examination of these properties not only contributes to fundamental knowledge but also provides crucial insights for the rational design of emissive materials in prospective applications. In this context, this work conducts an in-depth analysis of four families of 4,6-bis(arylvinyl)pyrimidines, evaluating the influence of substituents on both the aryl groups and position 2 of the pyrimidine ring. While previous research has primarily focused on solution studies, this work emphasizes the importance of examining solid-state photophysics. Through a multidisciplinary approach encompassing optical techniques, x-ray diffraction, and quantum chemical calculations, a comprehensive understanding of the structure-property relationships is achieved. This study underscores the intricate interplay between molecular structure, aggregation, and fluorescence behavior in pyrimidines, offering valuable insights with broader implications beyond academic realms.

Assembly of Eosin Y in-situ intercalated Zr-MOF composite for decontaminating Cr(VI) and reactive dyes via physical capture and photochemical purification

Post-modification based on highly water stable Zr-MOF introduces a novel dimension of functional regulation, offering a fresh perspective for the advancement of pragmatic photocatalysts in the water treatment field. In this study, an entirely novel Zr-MOF (NU-1400-py), featuring a topological network identical to that of NU-1400, has been assembled. The main difference is the replacement of TPTC's central benzene ring with a pyrimidine ring. Utilizing the inherent porosity and semiconducting properties, this Zr-MOF possesses the capability to physically trap Cr2O72- ions (136.43 mg/g), achieving photochemical purification of Cr(VI) and K-, X-, M-type reactive dyes from water. Moreover, another novel heterojunction material EY@Zr-MOF, has been fabricated via in-situ intercalation of luminescent Eosin Y (EY) species within Zr-MOF. Due to the sensitization of embedded EY molecules, EY@Zr-MOF exhibits significantly optimized interface resistance, transient photocurrent intensity and carrier migration efficiency compared to pristine Zr-MOF. Notably, the photochemical purification efficiencies of EY@Zr-MOF towards Cr2O72- (99.66 %, 30 min), RB13 (90.18 %, 120 min), RR2 (92.40 %, 300 min) and RR11 (84.80 %, 90 min) have been dramatically elevated, offering the considerably accelerated reaction kinetics of 1.24, 4.82, 2.48 and 6.23 times, respectively, compared to pristine Zr-MOF, the photochemical purification efficiencies of Zr-MOF towards Cr2O72- (97.88 %, 30 min), RB13 (85.55 %, 450 min), RR2 (71.38 %, 450 min) and RR11 (53.16 %, 240 min). Additionally, its photocatalytic REDOX mechanisms in eliminating target contaminants were proposed tentatively. This contribution offers a viable pathway for designing multi-functional materials aimed at solving some intractable environmental issues caused by Cr(VI) and reactive dyes.

Thiamine-modified octamolybdate catalyzes solvent-free stereoselective olefin epoxidation with TBHP

Simple stirring of an acidic aqueous solution (pH=3) containing sodium molybdate and thiamine hydrochloride (VB1) at room temperature resulted in an octamolybdate-containing VB1 (MoB1) material as an efficient and cost-effective epoxidation catalyst using tert‑butyl hydroperoxide (TBHP) under solvent-free condition. The stereospecific stilbene oxidation (>99 %) observed in the presence of MoB1 can be originated from the steric hindrance of some groups on the thiamine molecule and π–π stacking interactions of its pyrimidine and/or thiazole rings with phenyl rings of stilbenes. Further olefins such as cyclooctene, indene, 1-octene, and styrenes are efficiently oxidized using MoB1/TBHP catalytic system. The catalyst is composed of two thiaminium dications (C12H18N4OS)2+ and one Mo8O264– tetraanion based on different characterization techniques and chemical compositional analyses. Field Emission Scanning Electron Microscope (FE-SEM) images shows a sheet-like nanostructure for MoB1 comprising layers with thicknesses ranging from 50 to 500 nm. It exhibits a heterogeneous nature in catalysis evidenced by hot filtration test and ICP-OES analysis. X-ray photoelectron spectroscopy (XPS) indicates minor contributions of Mo in the oxidation states +V and +IV in addition to MoVI attributed to partial electron transfer from VB1 to Mo8O264–. The scavenging experiments support the presence of radical species during catalysis, while, they do not damage the structural integrity of the MoB1 catalyst based on the recycling experiments and FT-IR spectra.

Tunable Emission and Structural Insights of 6-Arylvinyl-2,4-bis(2'-hydroxyphenyl)pyrimidines and Their O∧N∧O-Chelated Boron Complexes.

In this study, we present the synthesis and photophysical characteristics of a novel series of 6-arylvinyl-2,4-bis(2'-hydroxyphenyl)pyrimidines. These compounds exhibit nonemissive properties attributed to the potential occurrence of a excited-state intramolecular proton transfer process from the OH groups to the nitrogen atoms of the pyrimidine ring. The introduction of an acid for protonation of the pyrimidine ring results in a significant enhancement of the fluorescence response, easily perceptible to the naked eye. Notably, these molecules serve as intriguing rigid O∧N∧O ligands for boron chelation. The incorporation of boron atoms promotes structural planarity, increases rigidity, and successfully restores fluorescence in both solution and the solid state. Moreover, the photoluminescence was found to be strongly influenced by the nature of the end groups on the arylvinylene fragment, allowing for the modulation of the emission color and covering the optical spectrum from blue to red. Strong emission solvatochromism was observed in various solvents, a finding that supports the formation of intramolecular charge-separated emitting states, particularly when terminal electron-donating groups are present in the structure. X-ray diffraction analysis enables the determination of inter- and intramolecular interactions, as well as molecular packing structures, aiding in the rationalization of distinct luminescent behaviors in the solid state. All experimental findings are elucidated through extensive density functional theory (DFT) and time-dependent DFT calculations.

Molecular Modeling Studies to Mimic the Binding Hypothesis of NEU3 Sialidase and EGFR in Nonsmall Cell Lung Carcinoma

The activation of the Neuraminidase 3 (NEU3) enzyme has been associated with the hyperphosphoryla-tion of Epidermal Growth Factor Receptor (EGFR) in Nonsmall Cell Lung Carcinoma (NSCLC). Existing EGFR inhibitors (such as gefitinib, erlotinib, lapatinib, icotinib, afatinib and osimertinib) reduce the hyperactivation of downstream signaling pathways (Akt, Mapk, Jak-Stat, Plc) but fail to completely abolish EGFR hyperphosphorylation. Therefore, co-targeting NEU3 and EGFR presents a greater potential to be used as a combinatorial therapy for NSCLC. This study employs structure guided approaches to elucidate the binding hypothesis of NEU3 and EGFR inhibitors. Toward this, important 3D features associated with high inhibitory potency of NEU3, and EGFR modulators were identified through SAR. The triazole substitution in acetamide dihydropyran carboxylic acid derivatives is mainly responsible for improved inhibitory potency against NEU3. Therefore, the hydrophobic ([Formula: see text]-H) interaction with the benzene ring and hydrogen bonding with the hydroxyl group of triazole are critical for designing new NEU3 modulators. Molecular Dynamics (MD) simulation studies demonstrate the stability of hydrogen bonding interactions of highly active NEU3 inhibitors with Pro66, Gly199 and Glu410 residues. Similarly, pyrimidine ring of EGFR inhibitors forms stable hydrogen bonds with Lys721 and Asp831 residues, contributing to their inhibitory potency. Our findings suggest that incorporating these identified 3D features associated with triazole and pyrimidine substitutions into a suitable scaffold could be a valuable strategy for developing a new generation of NEU3 and EGFR modulators. This approach offers a potential multi-targeted therapy for NSCLC patients.

Developments of Pyrrolo[2,3-d]pyrimidines with Pharmaceutical Potential

: In terms of fused heterocyclic compounds, pyrrolopyrimidines, and their substituted analogs are among the most extensively explored scaffolds. Based on the location of the nitrogen atom in the pyrrole ring, pyrrolopyrimidines have different isomers. This study deals only with the pyrrolo[2,3-d]pyrimidine isomer. Several techniques are represented and discussed in this review for producing pyrrolo[2,3-d]pyrimidine derivatives. The first one is the cyclization of the pyrimidine ring on the pyrrole ring through the reaction of β-enaminonitrile, β-enaminoester or β-enaminoamide of the pyrrole ring with different bifunctional reagents such as formic acid, acetic acid, acetic anhydride, formamide, isothiocyanate, urea, thiourea, and carbon disulfide. The second technique includes cyclization of the pyrrole ring on the pyrimidine ring via the treatment of pyrimidine, aminopyrimidine, diamino-pyrimidine, or triamino-pyrimidine with different reagents such as nitroalkenes, alkynes, aldehydes, and acid chlorides. In addition, different reaction methodologies like one pot, two-step, and threestep synthetic methodologies were reported. The last technique for producing pyrrolo[2,3-d]pyrimidine derivatives is through miscellaneous reactions. This review also includes the interactions of pyrrolo[2,3- d]pyrimidines at different active centers of the pyrrole ring with different reagents to form N-alkylated, Nglycosylated, C-5, and C-6 adducts. Besides, the interactions on the pyrimidine ring to form chloro, hydrazino, and amino-imino derivatives were also discussed. The amino-imino derivatives are key intermediates for the preparation of tricyclic pyrrolotriazolopyrimidines. Finally, the pharmaceutical and biological properties of some pyrrolo[2,3-d]pyrimidine derivatives have also been mentioned. This information can be utilized to design novel diverse pyrrolopyrimidine derivatives for recent challenges in pharmaceutical and medical studies to develop the already existing drugs or discover new ones.

Access to Seleno‐Functionalized Thiazolo[3,2‐a]Pyrimidinones and Pyrimido[2,1‐b][1,3]Thiazinones via Selenocyclization of 2‐Alkenylthiopyrimidinones and Their Fused Analogs

AbstractThe methodology of electrophilic selenylation/cyclization of 2‐alkenylthiopyrimidinones and their fused analogs underlies most of the reported synthetic approaches to seleno‐functionalized thiazolo[3,2‐a]pyrimidinones and pyrimido[2,1‐b][1,3]thiazinones. We have developed a novel implementation of this strategy using as reagent phenylselenyl chloride or the visible‐light‐induced radical‐generating (PhSe)2/CBr4 system. The effect of the unsaturated substrate structure and reaction conditions on the selenocyclization regioselectivity has been revealed and analyzed in detail. It has been established that regardless of the conditions used, 2‐allylthiopyrimidinones react with selenylating agents via electrophilic 5‐exo‐trig cyclization mainly involving the N1 nitrogen atom to give selenium‐containing thiazolo[3,2‐a]pyrimidinones as major products. On the contrary, the selenocyclization with 2‐cinnamylthiopyrimidinones is dominated by the 6‐endo‐trig mode: it mostly involves six‐membered ring closure at the N1 or N3 atom thus leading to selenylated pyrimido[2,1‐b][1,3]thiazinones, with the regiochemistry governed by the position and nature of the substituents on the substrate pyrimidine ring. However, some of the fused cinnamylthio‐substituted substrates yield 5‐exo‐trig cyclized products in the LiClO4/МеNO2 system (a sufficiently polar solvent with a strong electrolyte added).

S‐Tetrazine‐Bridged 2,2′‐Bipyrimidine as Superior Atom‐Economic Multi‐Charge Cathode Material for Lithium‐Ion Batteries

AbstractNitrogen‐containing heterocyclic molecules feature metal resource‐independence, flexible conjugation structure and fast charge storage kinetics, making them promising to be used as the electrode material in lithium‐ion batteries. However, an insufficiently high capacity (<400 mAh g−1) seriously threatens their practical application. Herein, a novel molecule, viz. 3,6‐bis(2‐pyrimidinyl)‐1,2,4,5‐tetrazine (DPmT), is developed by inserting an electron‐withdrawing π‐bridge unit of s‐tetrazine between two pyrimidine rings, in which a dense assembly of multiple active sites is realized. The DTmP exhibits a remarkable atom economy of 40 g (mol e)−1, which refers to the molecule mass per unit of charge transferred. The cathode material of DPmT yields a high capacity of 653 mAh g−1 and an energy density of 1188 Wh kg−1 at 50 mA g−1 at 70 °C. And 80% capacity retention is achieved after 500 cycles at 500 mA g−1, confirming its superior cyclability. Spectroscopy studies and theoretical calculations are performed to investigate the charge storage process. First, the C═N and N═N are claimed as plausible binding sites for the lithium ions. Second, the introduction of s‐tetrazine significantly enhances molecular planarity, thereby promoting charge delocalization and molecular stability. This work provides a novel strategy for designing atom‐economic multi‐charge electrode materials with high capacity.

Design, synthesis and structure-activity relationship of novel 2-pyrimidinylindole derivatives as orally available anti-obesity agents

Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC50 value of 0.07 μM and showed relatively low cytotoxicity with an IC50 value of around 24 μM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity.

Synthesis and crystal structures of disubstituted ferrocenes carrying bromo and N-heteroaryl substituents

Noncovalent interactions in crystal packing play significant roles in the formation of extended network structures. Thus, this study aims to investigate the influence of noncovalent bonds, particularly halogen bonds, on the crystal packing of ferrocene derivatives. For this purpose, disubstituted ferrocene derivatives carrying both bromo and N-heteroaryl substituents, 1‑bromo-1ʹ-(Het)ferrocene [Het = 5-pyrimidyl (1), 2-pyridyl (2), and 4-pyridyl (3)] and 1‑bromo-2-(Het)ferrocene [Het = 5-pyrimidyl (4) and 4-pyridyl (6)], were synthesized. Here, we discuss a comparison of their molecular and crystal structures, with those of a related compound, 1‑bromo-2-(2-pyridyl)ferrocene (5). Although the crystal packings of 1–5 are classified into quasi-one-dimensional chain structures, their intermolecular interactions are different. Compounds 1–3 exhibit Br⋅⋅⋅cyclopentadienyl halogen bonds to form extended structures. In contrast, 4 shows the π–π stacking interactions between the pyrimidine rings of adjacent molecules, and 5 exhibits the Br⋅⋅⋅N halogen bonds between adjacent molecules. The crystal structures contained chiral molecules of opposing handedness.

Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory Mechanisms of AKT, CDK9, and TNKS2 by a Novel 2-phenylquinazolinone Derivative in Cancer Therapy- An In-silico Investigation Therapy.

Blocking the oncogenic Wnt//β-catenin pathway has of late been investigated as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain members of the tankyrase-kinase family; Tankyrase 2 (TNKS2), Protein Kinase B (AKT), and Cyclin- Dependent Kinase 9 (CDK9), which propagate the oncogenic Wnt/β-catenin signalling pathway. During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one was repurposed to serve as a 'triple-target' inhibitor of TNKS2, AKT and CDK9. Yet, the molecular mechanism that surrounds its multi-targeting activity remains unanswered. As such, this study aims to explore the pan-inhibitory mechanism of 2-(4-aminophenyl)-7-chloro-3H-quinazolin- 4-one towards AKT, CDK9, and TNKS2, using in silico techniques. Results revealed favourable binding affinities of -34.17 kcal/mol, -28.74 kcal/mol, and -27.30 kcal/mol for 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards TNKS2, CDK9, and AKT, respectively. Pan-inhibitory binding of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one is illustrated by close interaction with specific residues on tankyrase-kinase. Structurally, 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one had an impact on the flexibility, solvent-accessible surface area, and stability of all three proteins, which was illustrated by numerous modifications observed in the unbound as well as the bound states of the structures, which evidenced the disruption of their biological function. Prediction of the pharmacokinetics and physicochemical properties of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4- one further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties. The following structural insights provide a starting point for understanding the paninhibitory activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one. Determining the criticality of the interactions that exist between the pyrimidine ring and catalytic residues could offer insight into the structure-based design of innovative tankyrase-kinase inhibitors with enhanced therapeutic effects.

Design, Antimicrobial Testing, and Molecular Docking Studies of New Chalcone and Pyrimidine Derivatives based on 2-phenyl-1H-pyrazol-3(2H)-one

Background & Objectives: Heterocyclic pyrimidine and pyrazole rings have attracted the interest of medicinal chemists because of their pharmacological potential including antimicrobial activity. Based on molecular hybridization, new chalcones 6a-g and pyrimidines 7a-g based on a pyrazole scaffold were designed. Methods: The synthesis of these compounds involved mild condensation reactions between compound 4 and various aromatic aldehydes in a mixture of ethanol/NaOH (95:5 v/v) to give the corresponding chalcones 6a-g. These chalcones were further reacted with urea in the presence of a base in ethanol to produce the pyrimidine derivatives 7a-g. These new candidates were screened for their in vitro antimicrobial activities and molecular docking studies were evaluated. Results: The antibacterial and antifungal studies of all synthesized compounds against the strains tested showed that compounds 6c, d, and 7c, d exhibited the highest antibacterial and antifungal activities. In addition, the structure-activity relationship and docking studies are discussed. Conclusion: The synthesized compounds 6c, 6d, 7c, and 7d showed the highest antibacterial and antifungal activities against the tested strains.

Biochemical insights into the biodegradation mechanism of typical sulfonylureas herbicides and association with active enzymes and physiological response of fungal microbes: A multi-omics approach

The extensive use of sulfonylurea herbicides has raised major concerns regarding their long-term soil residues and agroecological risks despite their role in agricultural protection. Microbial degradation is an important approach to remove sulfonylureas, whereas understanding the associated biodegradation mechanisms, enzymes, and physiological responses remains incomplete. Based on the rapid biodegradation of nicosulfuron by typical fungal isolate Talaromyces flavus LZM1, the dependency on cellular accumulation and environmental conditions, e.g. pH and nutrient supplies, was shown in the study. The biodegradation of nicosulfuron occurred intracellularly and followed the cascade of reactions including hydrolysis, Smile contraction rearrangement, hydroxylation, and opening of the pyrimidine ring. Besides 2-amino-4,6-dimethoxypyrimidine (ADMP) and 2-aminosulfonyl-N,N-dimethylnicotinamide (ASDM), numerous products and intermediates were newly identified and the structural forms of methoxypyrimidine and sulfonylurea bridge contraction rearrangement are predicted to be more toxic than nicosulfuron. The biodegradation should be enzymatically regulated by glycosylphosphatidylinositol transaminase (GPI-T) and P450s, which were manifested with the significant upregulation in proteomics. It is the first time that the hydrolysis of nicosulfuron into ADMP and ASDM have been associated with GPI-T. The integrated pathways of biodegradation were further elucidated through the involvement of various active enzymes. Except for the enzymatic catalysis, the physiological responses verified by metabolo-proteomics were critical not only to regulate material synthesis, uptake, utilization, and energy transfer but also to maintain antioxidant homeostasis, biodegradability, and tolerance of nicosulfuron by the differentially expressed metabolites, such as acetolactate synthase and 3-isopropylmalate dehydratase. The obtained results would help understand the biodegradation mechanism of sulfonylurea from chemicobiology and enzymology and promote the use of fungal biodegradation in pollution rehabilitation.

Comparison of the crystal structures of the JAK1/2 inhibitor ruxolitinib and its hydrate and phosphate.

Ruxolitinib {RUX; systematic name: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, C17H18N6} is an orally bioavailable JAK1/2 inhibitor approved for treating intermediate- or high-risk myelofibrosis (MF) and high-risk polycythemia vera (PV). Recent patents claim that RUX can exist in many different forms, information for which is important for the clinical utilization of RUX, especially for the formulation and bioavailability of the drug. But there has been no detailed study on its forms so far. Herein crystals of RUX and its dihydrate (RUX-2H; C17H18N6·2H2O) and phosphate (RUX-P; systematic name: 4-{1-[(1R)-2-cyano-1-cyclopentylethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-3-ium dihydrogen phosphate, C17H19N6+·H2PO4-) were prepared successfully and their structures studied in detail for the first time. Our study shows that the three crystals of RUX differ in the orientation of the pyrimidine ring relative to the pyrazole ring of the RUX molecule, and in their hydrogen-bond interactions. The water molecules in RUX-2H and the dihydrogen phosphate anion in RUX-P enrich the hydrogen-bond networks in these forms. The expected proton transfer occurs in RUX phosphate and the protonated N atom is engaged in a charge-assisted hydrogen bond with the counter-anion. Hydrogen-bonding interactions dominate in the crystal packing of the three forms. The detailed conformations and packing of the three forms were compared through the calculation of both Hirshfeld surfaces and fingerprint plots.

Pyrimidine-based sulfonamides and acetamides as potent antimicrobial Agents: Synthesis, Computational Studies, and biological assessment

A series of novel sulfonamide and acetamide derivatives of pyrimidine were synthesized and their antimicrobial activities were assessed. Based on the Microbroth dilution method, the minimum inhibitory concentration (MIC) of the synthesized compounds demonstrated moderate to good levels of antifungal and antibacterial activity. Structure-activity relationship analysis suggested that the presence of electron-withdrawing groups, such as halogens, nitrile, and nitro groups, on the pyrimidine ring contributed to the enhanced antimicrobial potency, while electron-donating substituents led to a decrease in activity. Computational studies, including density functional theory (DFT), frontier molecular orbitals (FMO), and molecular electrostatic potential (MEP) analysis, provided insights into the electronic properties and charge distribution of the compounds. Drug-likeness evaluation using ADME/Tox analysis indicated that the synthesized compounds possess favorable physicochemical properties and could be potential drug candidates. Molecular docking against the Mycobacterium TB protein tyrosine phosphatase B (MtbPtpB) revealed that the synthesized compounds exhibited strong binding affinities (−46 kcal/mol to − 61 kcal/mol) and formed stable protein–ligand complexes through hydrogen bonding and π-π stacking interactions with key residues in the active site. The observed interactions from the docking simulations were consistent with the predicted interaction sites identified in the FMO and MEP analyses. These findings suggest that the synthesized pyrimidine derivatives could serve as promising antimicrobial agents and warrant further investigation for drug development.

Synthesis and histone deacetylases inhibitory activity of pyrimidine‐based 1,3,4‐oxadiazoles

AbstractThe histone deacetylases (HDACs) are being explored as a promising therapeutic target for the treatment of various diseases. Here, the synthesis of a series of pyrimidine‐based 1,3,4‐oxadiazoles, in which the oxadiazole scaffold is attached to the pyrimidine ring via a methyleneoxy spacer, is described and their HDAC inhibitory activity studied. The target compounds were synthesized by sequence of reactions involving O‐alkylation of 2‐(methylthio)pyrimidin‐4(3H)‐ones with ethyl 2‐bromoethanoate followed by oxidation of the 2‐methylthio group, displacement of the obtained 2‐methylsulfonyl group with amines, hydrazinolysis of the obtained ethyl (2‐amino‐substituted pyrimidin‐4‐yloxy)acetates to give the corresponding hydrazides and their cyclization under the treatment with ethyl O‐ethyl xanthate or carbonyldiimidazole to 1,3,4‐oxadiazole‐2(3H)‐thiones and 1,3,4‐oxadiazol‐2(3H)‐one, correspondingly. In addition, two 1,3,4‐oxadiazole‐2(3H)‐thiones were converted into (N3)‐morpholinomethyl derivatives by the Mannich reaction with formaldehyde and morpholine. The yields of intermediates and target compounds ranged from moderate to excellent. The synthesized compounds were characterized by 1H and 13C NMR spectra and HRMS data, their purity was controlled by TLC. The synthesized pyrimidine‐based 1,3,4‐oxadiazoles (18 compounds) were tested as inhibitors of the HDAC4 and HDAC8 isoforms and their inhibitory activity was compared with that of Vorinostat. Most of the oxadiazolethiones containing methyl group at the position 6 of the pyrimidine moiety were found to be more selective towards HDAC8, while oxadiazolethiones with propyl group in the pyrimidine ring were active against HDAC4. Among the tested compounds, 5‐((2‐(dibutylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (48) was found to have the strongest inhibitory activity for HDAC4 isoform (IC50 = 4.2 μM vs. IC50 = 59 μM for Vorinostat) while 5‐((2‐(cyclopentylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3H)‐thione (50) was the most potent HDAC8 inhibitor (IC50 = 6.8 μM).