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A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors as antidiabetic agents. Chemical structure of all new compounds were confirmed by different spectroscopic methods. The designed compounds were evaluated using a MAK 203 kit as DPP4 inhibitors in comparison with Sitagliptin. The biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety of 6-bromo quinazoline ring had promising inhibitory activity with IC50 = 9.25 ± 0.57 µM. The toxicity test of all compounds confirmed safety profile of them. Kinetic studies showed that compound 9i exhibited a competitive-type inhibition with a Ki value of 12.01 µM. Computational approach supported the rationality of our design strategy, as 9i represented appropriate binding interactions with the active sites of DPP4 target. MD simulation outputs validated the stability of ligand 9i at DPP4 active site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, and theoretical IR spectrum was employed to study the reactivity descriptors of 9i and 9a as the most and least potent compounds respectively. Based on the DFT study, compound 9i was softer and, as a result, more reactive than 9a. Taken together, our results showed the potential of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives as promising candidates for developing some novel DPP4 inhibitors for managing of type 2 diabetes. [ABSTRACT FROM AUTHOR]

This study describes a simple, inexpensive, and effective method for the synthesis of new 5‐imino‐7‐aryle‐5H‐thiazolo[3,2‐a]pyrimidine‐3‐carbonitrile derivatives 4a‐e using a green procedure that does not require the use of heat or a base, creating a strategy that meets both economic and environmental demands. Various synthesized products were characterized via diverse techniques such as 1H‐NMR, infrared (FT‐IR), Mass spectroscopy (MS), and single crystal X‐ray diffraction. Using a fluorescence spectrometer, the 5‐imino‐7‐phenyle‐5H‐thiazolo[3.2‐a]pyrimidine‐3‐carbonitrile 4a has been tested as a potent fluorescent agent in mixture of DMSO/Water at 10−4 M in one hand, and on the other hand the results of our fluorescence evaluation studies with metal ions (Pb(II), Ba(II), Cd(II), Ni(II), Mn(II), Hg(II), Zn(II), Fe(II), Co(II), Cu(II), La(II), Cr(III), and Fe(III)) have shown that this compound exhibits a turn‐on and turn‐off of the fluorescence to 4a compound with these metals, what forms poor to good interaction by these ions. This result represents the emergence of a new potential ligand for the two heavy cations Cd(II) and Pb(II), which are toxic and polluting, and whose detection is currently of high interest. As well, In the molecular docking evaluation study, it was determined that the 4e molecule has an exceptional ability to inhibit the binding energy of the tubulin protein by −9.13 kcal/mmol, compared to other compounds. The results demonstrate the possibilities for a novel oral medication application. [ABSTRACT FROM AUTHOR]

In view of the extremely important biological and medicinal properties of napthofurans, the synthesis of these heterocycles has fascinated the interest of medicinal and organic chemists. Keeping this in mind, we herein report the synthesis and antimicrobial evaluation of 4-N-aryl-naphtho[2,1-b]furo[3,2-d] pyrimidines 5 (a–l). Structures of these synthesized compounds were confirmed by spectral analysis like IR, NMR, and Mass spectrometry. The in vitro antimicrobial activities were reported for all the compounds 5 (a–l). The compounds 5e and 5f exhibited excellent antibacterial, antifungal, and antidermatophytic activities against tested pathogens at MIC 3.125, and 3.125 µg/mL, respectively. Furthermore, molecular docking studies of these compounds against S. aureus tyrosyl-tRNA synthetase (PDB ID: 1JIJ), S. aureus Gyrase (PDB ID: 2XCT), and SARS-CoV-2 Omicron (PDB ID: 7TOB), revealed the potential binding mode of the ligands to the site of the appropriate targets. Finally, drug-likeness and structure-activity relationship studies were also disclosed. [ABSTRACT FROM AUTHOR]

A wide range of bioactive compounds have been created using the versatile pharmacophore pyrimidine. In order to improve biological applications, we, therefore, envisioned adding these privileged moieties. In this work, we developed an efficient 2-aminopyrimidine derivatives. We further investigated the anticancer activity of all the compounds against colon cancer cell lines COLO-205 and HT-29. Out of several compounds synthesized, two compounds SD2 and SD4 have shown comparable potent anticancer activity when compared to standard Cabozantinib. The most potent cytotoxic compound against colon cancer cells in our study was found to be SD2 with an IC50 value of 9.57 μ M. The investigation from molecular docking showed the best binding affinity. The complex stability within an enzyme's pocket was demonstrated by the molecular dynamic simulation running for 100 ns. The work intends to critically search 2-aminopyrimidine derivatives for anticancer activity in two colon cancer cell lines (HT-29 and COLO-205). Advanced computational studies are carried out to provide more insight. Two compounds showed comparative anticancer activity in cytotoxicity and molecular modeling studies with standard. [ABSTRACT FROM AUTHOR]

Compound 4, a Schiff base‐containing pyrimidine moiety, was synthesized from the reaction of N‐amino pyrimidine derivative with 4‐fluorobenzaldehyde. The molecular and crystallographic structure of 4 was determined by the SC‐XRD method. According to these results, compound 4 crystallized in the triclinic P‐1 space group, and the stability of its crystal structure was ensured through intermolecular C−H⋅⋅⋅π and π⋅⋅⋅π interactions. In addition to the antibacterial effects of the molecule on some Gram‐positive and Gram‐negative bacteria, the inhibition of biofilm formation in P. aeruginosa PAO1 and the production of violacein pigment in Chromobacterium violaceum (C. violaceum) 12472 were studied. The results demonstrated that compound 4 had strong effectiveness in preventing the formation of biofilms produced by PAO1 with an inhibition rate of 69 %. Extensive theoretical calculation studies of molecule have been conducted and the molecular structure of 4 has been optimized in the ground state using density functional theory (DFT). The investigated compound's frontier molecular orbitals, chemical parameters, and molecular electrostatic potential surfaces were examined. Molecular docking studies were performed to explain the binding interaction 4 with the high inhibitory effect against C. violaceum phenylalanine hydroxylase D139A (PDB ID: 4Q3Y), D139E (PDB ID: 4Q3W), D139K (PDB ID: 4Q3Z), and D139N (PDB ID: 4Q3X) mutations. [ABSTRACT FROM AUTHOR]

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR, 1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC50 = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50 values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors. [ABSTRACT FROM AUTHOR]

A convenient synthetic protocol for diverse 4, 5-disubstituted-6-methyl-2-(methylthio)pyrimidines was successfully developed by Sonogashira reactions. In the presence of Pd-Cu catalysts, one-pot, multi-step reaction of amines, terminal alkynes, and 4-chloro-5-iodo-6-methyl-2-(methylthio)pyrimidine in DMF at 80°C resulted in 4, 5-disubstituted-6-methyl-2-(methylthio)pyrimidine derivatives in moderate to good yields. [ABSTRACT FROM AUTHOR]

The quest for and development of combinational chemotherapeutic medicines with various modes of action and low side effects is an essential element of cancer treatment. Aside from developing wholly novel drugs with chemical properties that are obviously distinct from current ones, another strategy involves combining two or more pharmacophores into a sinSgle molecule. The method for making several 1,2,4-triazole derivatives is detailed in the scheme. By 5-Mercapto-3-pyrimidinyl-1,2,4 triazole with various substituted benzyl halides, a total of 7 distinct 1,2,4-triazole derivatives were obtained. Combustion Analysis, TLC, IR, MS and other methods were used to confirm the physical and analytical properties of the newly synthesized 1,2,4-triazole derivatives. Compounds TP1-TP7 exhibit IC50 values ranging from 41.12 M to 61.11 M, with compound TP6 having the greatest activity against the murine melanoma (B16F10) cell line. TP6 was discovered to have more strong anticancer action in anti-cancer screening. As a result, we believe that the findings of this study may pave the way for the creation of anticancer drugs with high efficacy and fewer side effects. As a result, 1,2,4-triazol-3-pyrimidine-based compounds may have a broad anticancer range and serve as a potential lead molecule in different malignancies. [ABSTRACT FROM AUTHOR]

Guanidine-containing molecules are an interesting class of compounds within both medicinal and material sciences. Having knowledge of their tautomerism is key in designing guanidines that interact with biological and chemical receptors. However, there are limited data on the solid-phase structure of N,N′-substituted guanidines. Thus, eleven guanidines bearing a 4,6-dimethylpyrimidyl at one end and substituents of varying sizes and electronic properties at the other side, were synthesised, crystallised, and analysed by X-ray crystallography. Calculations of isolated molecules of tautomer energies and bond lengths were performed for comparison. One class of guanidines crystallised as a cis–trans tautomer with the shorter bond directed towards the pyrimidyl unit. When more electron-deficient aniline substituents were inserted, the crystallised tautomer changed to a cis–cis form where the shorter bond was directed towards the aniline. The switch in the tautomer structure is concluded to be due to both the electronic properties of the substituents and the intermolecular hydrogen bonding in the crystal lattice. [ABSTRACT FROM AUTHOR]

In this work, two novel pyrimidine‐cored covalent organic frameworks TpTap‐COF and TpTan‐COF were synthesized for the first time and used for the adsorption of heavy metal ions in aqueous solution. Both COFs are nanofiber clusters with preferable crystallinity and thermal stability. The impact parameters such as pH value, shaking time, initial concentration, and temperature were studied by batch adsorption experiments in the multi‐metal ions system. The adsorption of six metal ions onto COFs follows the pseudo‐second‐order kinetic model and the Freundlich isotherm model, which is a chemical adsorption process that occurs on non‐uniform surfaces. The adsorption rate is determined by both film diffusion and intraparticle diffusion. Further research on the adsorption of copper ions onto COFs indicates the formation of metal complexes between O#N#N/O#O chelating sites in the COF skeleton and Cu ions through the sharing of lone pair electrons. [ABSTRACT FROM AUTHOR]

An original asymmetric achiral pyrimidine core molecule, with long carbon chains on one side and a coumarin fragment on the other, is designed. This advanced molecular structure enabled the spontaneous emergence of crystalline and liquid crystalline thin films with strong 2nd harmonic generation (SHG) without any corona polishing process or tedious deposition techniques. Moreover, pin‐pointed multiphoton absorption in the liquid crystalline phase effectively switches off the SHG signal locally and permanently, underlining its interest in 3D data storage. This prototypical material, which can be fully addressed by NLO processes, multiphoton writing, and SHG reading, paves the way for the development of efficient flexible materials for 3D optical data storage. [ABSTRACT FROM AUTHOR]

Background: Type-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medications to cure T2DM, the review of the literature found that various Pyrimidine derivatives act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic Beta-cells and its mechanism of action with fewer adverse effects. In the present research work, In-silico investigations were carried out to investigate the potential of the Pyrimidine analog as an agonist to the protein target GPR119 receptor. We performed exhaustive molecular modeling and protein modeling methodologies such as homology modeling, and molecular docking along with various drug designing tools such as 3D-QSAR and Pharmacophore Mapping to ascertain the design of better GPR119 agonists. Results: Based on in-depth computational studies, we designed new pyrimidine moiety and analyzed them for GPR119 receptor agonist and further explored the ADMET properties. Designed compounds were found to exhibit better-predicted activities as compared to reference compound. Conclusions: The current research on pyrimidine derivatives, using molecular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of − 11.696, − 9.314 and − 8.721, respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidates for the treatment of diabetes acting via the GPR119 agonist mechanism. [ABSTRACT FROM AUTHOR]

Glioblastoma, the most aggressive form of brain tumor, poses significant challenges in terms of treatment success and patient survival. Current treatment modalities for glioblastoma include radiation therapy, surgical intervention, and chemotherapy. Unfortunately, the median survival rate remains dishearteningly low at 12-15 months. One of the major obstacles in treating glioblastoma is the recurrence of tumors, making chemotherapy the primary approach for secondary glioma patients. However, the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms. Consequently, considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs. To tackle glioma, numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEKERK-MPAK. By targeting specific signaling pathways, heterocyclic compounds have demonstrated efficacy in glioma therapeutics. Additionally, key kinases including phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase, cytoplasmic tyrosine kinase (CTK), receptor tyrosine kinase (RTK) and lipid kinase (LK) have been considered for investigation. These pathways play crucial roles in drug effectiveness in glioma treatment. Heterocyclic compounds, encompassing pyrimidine, thiazole, quinazoline, imidazole, indole, acridone, triazine, and other derivatives, have shown promising results in targeting these pathways. As part of this review, we propose exploring novel structures with low toxicity and high potency for glioma treatment. The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier. By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics, we can maximize their therapeutic value and minimize adverse effects. Considering the complex nature of glioblastoma, these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles. [ABSTRACT FROM AUTHOR]

Abstract A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors as antidiabetic agents. Chemical structure of all new compounds were confirmed by different spectroscopic methods. The designed compounds were evaluated using a MAK 203 kit as DPP4 inhibitors in comparison with Sitagliptin. The biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety of 6-bromo quinazoline ring had promising inhibitory activity with IC50 = 9.25 ± 0.57 µM. The toxicity test of all compounds confirmed safety profile of them. Kinetic studies showed that compound 9i exhibited a competitive-type inhibition with a Ki value of 12.01 µM. Computational approach supported the rationality of our design strategy, as 9i represented appropriate binding interactions with the active sites of DPP4 target. MD simulation outputs validated the stability of ligand 9i at DPP4 active site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, and theoretical IR spectrum was employed to study the reactivity descriptors of 9i and 9a as the most and least potent compounds respectively. Based on the DFT study, compound 9i was softer and, as a result, more reactive than 9a. Taken together, our results showed the potential of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives as promising candidates for developing some novel DPP4 inhibitors for managing of type 2 diabetes.

Abstract Background Type-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medications to cure T2DM, the review of the literature found that various Pyrimidine derivatives act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic Beta-cells and its mechanism of action with fewer adverse effects. In the present research work, In-silico investigations were carried out to investigate the potential of the Pyrimidine analog as an agonist to the protein target GPR119 receptor. We performed exhaustive molecular modeling and protein modeling methodologies such as homology modeling, and molecular docking along with various drug designing tools such as 3D-QSAR and Pharmacophore Mapping to ascertain the design of better GPR119 agonists. Results Based on in-depth computational studies, we designed new pyrimidine moiety and analyzed them for GPR119 receptor agonist and further explored the ADMET properties. Designed compounds were found to exhibit better-predicted activities as compared to reference compound. Conclusions The current research on pyrimidine derivatives, using molecular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of − 11.696, − 9.314 and − 8.721, respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidates for the treatment of diabetes acting via the GPR119 agonist mechanism.

Nitrogen‐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. [ABSTRACT FROM AUTHOR]

In this work, a series of new diarylpyrimidine derivatives as microtubule destabilizers were designed, synthesized, and evaluated for anticancer activities. Based on restriction configuration strategy, we introduced the pyrimidine moiety containing the hydrogen-bond acceptors as c/s-olefin bond of CA-4 analogs to improve structural stability. Compounds 11a-t exerted antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and MCF-7), due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HSF cells, as evidenced by MTT assays. In mechanistic investigations, compound 11s remarkably inhibited tubulin polymerization and disorganized microtubule in SGC-7901 cells by binding to tubulin. Moreover, 11s caused G2/M phase cell cycle arrest in SGC-7901 cells in a concentration-dependent manner. Furthermore, molecular modeling analysis revealed that 11s interacts with tubulin through binding to the colchicine site. In addition, the prediction of physicochemical properties disclosed that 11s conformed well to the Lipinski's rule of five. This work offered a fresh viewpoint for the discovery of new tubulintargeting anticancer drugs. [ABSTRACT FROM AUTHOR]

Machine learning (ML) approaches have been developed to predict materials' corrosion inhibition efficiency, particularly pyrimidine compounds. Notably, the virtual sample generation (VSG) technique enhances prediction accuracy, a novel approach for handling small datasets in this context. The random forest model, the best-performing nonlinear algorithm, showed substantial accuracy improvement based on the increase in R2 value from 0.05 to 0.99 and the decrease in RMSE value from 5.60 to 0.42, after applying VSG. These results underscore the efficacy of the VSG technique in boosting the predictive performance of ML models, particularly in scenarios constrained by limited data availability. [ABSTRACT FROM AUTHOR]

A series of novel salts based on aromatic polyamines and 2,3-pyrazinedicarboxylic acid, such as C10H12N6O5 (1), C10H9ClN6O4 (2), C11H10N8O4 (3), and C14H17N16O5.5 (4) or 3,4-thiophenedicarboxylic acid, such as C10H10N4O4S (5), C10H9ClN4O4S (6), and C10H10N4O4S2 (7), were synthesized and characterized by single-crystal X-ray diffraction. All compounds crystallize in a monoclinic space group. The structure was subjected to complex Hirshfeld surface analysis, molecular electrostatic potential, enrichment ratio, and energy framework calculations. The influence of different cations on the packing of 3-carboxypyrazine-2-carboxylate and 4-carboxythiophene-3-carboxylate anions in the crystal lattice was studied. O...H/H...O interactions are the main contributor in all crystals. In addition, in a series of pyrazine-containing structures, N(C)...H/H...N(C) interactions have relevance, while in a series of thiophene-based compounds, C...H/H...C and S...H(O)/H(O)...S. In addition, Cl-based interactions are observed in compound 2. According to the enrichment ratio calculations, O...H/H...O and C...C are the most preferable interactions in all structures. The energy frameworks are dominated by the dispersive contribution, only in compound 3 is the electrostatic term dominant. The analyzed structures reveal intra- and intermolecular recurrent supramolecular synthons. In both series of crystals, the robust H-bonded centrosymmetric dimer R22(8) as homo- or as heterosynthon (in compounds 2, 3, 6, and 7) and the intramolecular synthon S(7) generated by O-H...O interactions (in compounds 2, 6, and 7) are present. The supramolecular patterns formed by π...π (C...C) and C-O(Cl,S)...C are also noticeable. Notably, a dual synthon linking the supramolecular chain via π...π interactions and the homosynthon R22(8) via N-H...N interactions is visible in both series of new salts. A library of H-bonding motifs at diverse levels of supramolecular architecture is provided. We extended the analysis of intramolecular H-bonding motifs to similar structures deposited in the Cambridge Structural Database. Another important feature is the existence of an intramolecular O...H...O bridge between two neighboring carboxylic groups as substituents in anions in compounds 3 and 5. In this context, we performed quantum theory of atoms-in-molecule calculations to reveal more details. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the second leading cause of cancer‐related mortality in women, and targeting biological pathways such as the JNK pathway has proven to be a viable therapeutic target for BC therapy. Here, we synthesized piperazin‐2‐yl‐pyrimidines and evaluated them for anticancer activity against MCF‐7 cells. In addition, antioxidant, reactive oxygen species (ROS) inhibition, caspase activity, and toxicity in platelets were studied in the presence and absence of active compound IA‐6 or IA‐7. Our detailed experimental analysis found that the compound IA‐7 showed anticancer activity by either activating p‐JNK or by inducing radical species in cancer and thrombosis model. Evident to in vitro analysis, the structure based molecular interaction studies of binding of IA‐7 to JNK3S exhibited a significant binding energy of −7.56 kcal/mol which was found to be a better binder when compared to previously reported JNK inducer (PC‐12). Overall, we herein report the analytically pure IA‐7 as lead structure that could be used as a template to develop target based anticancer agents where JNK modulation is predominant. [ABSTRACT FROM AUTHOR]

MOF supported on the red soil was synthesized thru simple method by Cu˗MOF and red soil with ratio of 1 : 5. The structure and morphology of MOF supported on the red soil was considered by FTIR and Raman spectroscopy, FESEM, TGA and BET methods. The results showed MOF supported on the red soil have mesoporous nanostructure (20–25 nm). A simple and efficient synthesis of tetrazolo[1,5-a]pyrimidines was accomplished by three-component reaction of a mixture of aromatic aldehyde, 5-aminotetrazole and ethyl acetoacetate or methyl acetoacetate using MOF supported on the red soil as heterogenic catalyst. The reactions were carried out in water and ethanol at 70°C. MOF supported on the red soil operated as a sufficient recyclable, effective, low cost and eco-friendly catalyst for synthesis of tetrazolo [1,5-a] pyrimidines. [ABSTRACT FROM AUTHOR]

In order to create Pyrrolo pyrimidine derivatives, multicomponent reactions involving butanoates, aldehydes, guanidine, activated acetylenic compounds, and ethyl bromopyruvate were carried out in water at room temperature with catalytic amounts of Cu@KF/CP NPs as a high-performance catalyst. Additionally, experiments involving the reducing power of ferric ions and radical trapping by DPPH were conducted to investigate the antioxidant capacity. As a result, the produced compounds exhibit excellent DPPH radical trapping and good ferric ion reduction capacity. The current method offers advantages including good reaction yield, green media, and simple product and catalyst separation. The pyrimidine ring is an aza-aromatic scaffold that can be found in many molecules of biological or pharmaceutical interest. Multicomponent reactions (MCRs) are a more interesting type of reaction due to mixing three or more reactants in one-pot and generating one product. They are also more economically useful and environmentally secure than multi-step methods. Carrying out the synthesis of organic compounds in water media is very interesting because water is a cheap solvent more readily available in large amounts. [ABSTRACT FROM AUTHOR]

The present study is devoted to describing the "logic" implicit in the standard genetic code. Bases are considered as physicochemical entities possessing two essential properties: molecular type and number of Hydrogen bonds involved (bases pairing) in the codon-anticodon specific interactions. It is proposed that the codon structure possesses a dual informative function: on the one hand, it determines its discriminating or non-discriminating character, and on the other hand, it determines a specific amino acid. These two aspects constitute the codon global information. Two different sets of rules are introduced to describe these different phenomena. It is established that, depending on the type of base occupying the second position, only two or three of the six codon properties located at defined positions determine the discriminating or non-discriminating behavior. With regard to the amino acid determining function of the codons for different sets of synonymous (singlets, doublets, triplets, quadruplets, or sextets), the number of informative properties integrating the codon and their typical positions characteristically change. Based on the rules presented here, it can be postulated that a codon can be defined as an asymmetric informative entity, whose global informative capacity results from the spatially organized combination of the six properties assigned by the three bases. [ABSTRACT FROM AUTHOR]

Metabolic abnormalities contribute to the pathogenesis of obesity and its complications. Yet, the understanding of the interactions between critical metabolic pathways that underlie obesity remains to be improved, in part owing to the lack of comprehensive metabolomics studies that reconcile data from both hydrophilic and lipophilic metabolome analyses that can lead to the identification and characterization of key signaling networks. Here, the study conducts a comprehensive metabolomics analysis, surveying lipids and hydrophilic metabolites of the plasma and omental adipose tissue of obese individuals and the plasma and epididymal adipose tissue of mice. Through these approaches, it is found that a significant accumulation of ceramide due to inhibited sphingolipid catabolism, while a significant reduction in the levels of uridine monophosphate (UMP), is critical to pyrimidine biosynthesis. Further, it is found that UMP administration restores sphingolipid homeostasis and can reduce obesity in mice by reversing obesity‐induced inhibition of adipocyte hypoxia inducible factor 2a (Hif2α) and its target gene alkaline ceramidase 2 (Acer2), so as to promote ceramide catabolism and alleviate its accumulation within cells. Using adipose tissue Hif2α‐specific knockout mice, the study further demonstrates that the presence of UMP can alleviate obesity through a HIF2α‐ACER2‐ceramide pathway, which can be a new signaling axis for obesity improvement. [ABSTRACT FROM AUTHOR]

The presence of one or more fluorine atoms in six-membered nitrogen heterocycles significantly impacts their chemical and physical properties, making them important in various applications, including pharmaceuticals and agrochemicals. This review, therefore, surveys the recent advances (mostly from 2010 onwards) in the synthesis of fluorinated six-membered N-heterocyclic compounds, including both the use of fluorinated starting materials and the introducing of fluorine atoms in the heterocyclic core and in either case exploring the benefits of microwave-assisted processes. [ABSTRACT FROM AUTHOR]

Various bi- and polycyclic pyrimidine derivatives (including fused ones) containing different aza- and carbocyclic fragments have been synthesized via a modified Biginelli reaction. [ABSTRACT FROM AUTHOR]

The reactions of pyrazine, pyridazine, and pyrimidine with hydroxyl radicals are theoretically studied. The barrier heights obtained with different electronic structure methods indicate that the reactions can competitively proceed via either abstraction of a hydrogen atom by an OH radical or OH addition to carbon sites. However, the rate constants computed within the temperature range 200 to 1500 K suggest that tunneling play a role resulting in large branching ratios in favor of hydrogen abstraction channels at lower temperatures. [ABSTRACT FROM AUTHOR]

In the last past twenty years, research on luminescent platinum (II) complexes has been intensively developed for useful application such as organic light emitting diodes (OLEDs). More recently, new photoluminescent complexes based on diazine ligands (pyrimidine, pyrazine, pyridazine, quinazoline and quinoxaline) have been developed in this context. This review will summarize the photophysical properties of most of the phosphorescent diazine Pt(II) complexes described in the literature and compare the results to pyridine analogues whenever possible. Based on the emission color, and the photoluminescence quantum yield (PLQY) values, the relationship between structure modification, and photophysical properties are highlighted. Tuning of emission color, quantum yields in solution and solid state and, for some complexes, aggregation induced emission (AIE) or thermally activated delayed fluorescence (TADF) properties are described. When emitting OLEDs have been built from diazine Pt(II) complexes, the external quantum efficiency (EQE) values and luminance for different emission wavelengths and in some cases, chromaticity coordinates obtained from devices, are given. Finally, this review highlights the growing interest in studies of new luminescent diazine Pt(II) complexes for OLED applications. [ABSTRACT FROM AUTHOR]

Starting compound 1 was synthesized according to reference.1 Benzylidene thiazole pyrimidin-3(5H)-ones were synthesized reactions of 1 with bromoacetic acid and various aryl-aldehydes in the same vessel via one-step, unlike studies in the literature. Quantum chemical parameters and full geometry optimizations for all compounds were computed using DFT based on B3LYP. Cytotoxic action potential of synthesized compounds was evaluated using trypan blue dye exclusion and MTT assays in different cell lines including adenocarcinoma alveolar basal epithelial-like adherent A549 cells, the colon adenocarcinoma HT-29 cells, prostate adenocarcinoma DU-145 cells, and diploid ARPE-19 retinal pigment epithelial cells. Embryotoxicity and genotoxicity assessments were performed on pluripotent human embryonal carcinoma NT2 and human lymphocyte cells, respectively. Compound A1 exhibited good anticancer activity on A549 and DU-145 cell lines, and the compounds including A3, 4, 6, and 9 induced cytotoxicity on A549 cells. The compounds A1-10 also showed a good biosafety profile at relatively lower concentrations. [ABSTRACT FROM AUTHOR]

Mitochondria are energy producers in cells, which can affect viral replication by regulating the host innate immune signaling pathways, and the changes in their biological functions are inextricably linked the viral life cycle. In this study, we screened a library of 382 mitochondria-targeted compounds and identified the antiviral inhibitors of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the de novo synthesis pathway of pyrimidine ribonucleotides, against classical swine fever virus (CSFV). Our data showed that the inhibitors interfered with viral RNA synthesis in a dose-dependent manner, with half-maximal effective concentrations (EC50) ranging from 0.975 to 26.635 nM. Remarkably, DHODH inhibitors obstructed CSFV replication by enhancing the innate immune response including the TBK1-IRF3-STAT1 and NF-κB signaling pathways. Furthermore, the data from a series of compound addition and supplementation trials indicated that DHODH inhibitors also inhibited CSFV replication by blocking the de novo pyrimidine synthesis. Remarkably, DHODH knockdown demonstrated that it was essential for CSFV replication. Mechanistically, confocal microscopy and immunoprecipitation assays showed that the non-structural protein 4A (NS4A) recruited and interacted with DHODH in the perinuclear. Notably, NS4A enhanced the DHODH activity and promoted the generation of UMP for efficient viral replication. Structurally, the amino acids 65–229 of DHODH and the amino acids 25–40 of NS4A were pivotal for this interaction. Taken together, our findings highlight the critical role of DHODH in the CSFV life cycle and offer a potential antiviral target for the development of novel therapeutics against CSF. IMPORTANCE Classical swine fever remains one of the most economically important viral diseases of domestic pigs and wild boar worldwide. dihydroorotate dehydrogenase (DHODH) inhibitors have been shown to suppress the replication of several viruses in vitro and in vivo, but the effects on Pestivirus remain unknown. In this study, three specific DHODH inhibitors, including DHODH-IN-16, BAY-2402234, and Brequinar were found to strongly suppress classical swine fever virus (CSFV) replication. These inhibitors target the host DHODH, depleting the pyrimidine nucleotide pool to exert their antiviral effects. Intriguingly, we observed that the non-structural protein 4A of CSFV induced DHODH to accumulate around the nucleus in conjunction with mitochondria. Moreover, NS4A exhibited a strong interaction with DHODH, enhancing its activity to promote efficient CSFV replication. In conclusion, our findings enhance the understanding of the pyrimidine synthesis in CSFV infection and expand the novel functions of CSFV NS4A in viral replication, providing a reference for further exploration of antiviral targets against CSFV. [ABSTRACT FROM AUTHOR]

IntroductionWe developed and produced a new series of 4,6-diaryl-pyrimidines 9–29 as antiproliferative agents targeting EGFR/VEGFR-2.MethodsThe antiproliferative efficacy of the novel targets was assessed against a panel of 60 NCI cancer cell lines and four cancer cell lines in vitro.Results and DiscussionCompounds 14, 17, 19, 22, 25, and 29 demonstrated the greatest potency among the derivatives, with GI50 values between 22 and 33 nM; compounds 22 and 29 exhibited the highest potency, with GI50 values of 22 and 24 nM, respectively. We subsequently examined the most efficient derivatives as dual EGFR/VEGFR-2 inhibitors, finding that compounds 22 and 29 functioned as dual inhibitors. Moreover, 22 and 29 can act as apoptotic inducers by increasing Bax levels and decreasing levels of the anti-apoptotic protein Bcl2. At both 24- and 48-h intervals, the cell migration rates of compounds 22 and 29 were lower than those of untreated cells, according to the migration rate and wound closure percentage assessment. The wound closure rate reached 100% after 72 h of therapy with compound 22 but only 80% with compound 29. The docking study showed that compounds 22 and 29 had docking scores similar to those of Erlotinib and Sorafenib, co-crystallized ligands, for the EGFR and VEGFR-2 proteins. The experiments on lipophilicity showed that the new pyrimidines had a consistent result. This group of compounds has better biological activity in all the biological systems studied with low lipophilicity.

A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.

AbstractHerein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 μM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.

A novel series of dihydropyrimidine/sulphonamide hybrids 3a-j with antiinflammatory properties have been developed and tested as dual mPGES-1/5- LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound 3j was the most potent dual inhibitor with IC50 values of 0.92 ^M and 1.98 ^M, respectively. In vivo, anti-inflammatory studies demonstrated that compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-a, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives' binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation. [ABSTRACT FROM AUTHOR]

A new library of tetrazole rings with oxazole-pyrimidine derivatives (9a–j) has been developed and synthesized. All of the compounds were characterized using spectral data. These were then tested for in vitro anticancer activity against four human cancer cell lines: prostate cancer (PC3 & DU-145), lung cancer (A549), and breast cancer (MCF-7) using an MTT assay. Etoposide was chosen as the positive control. Most of the compounds demonstrated moderate to good activity. These compounds (9a, 9b, 9d, 9g, and 9h) demonstrated the most powerful action. Particularly, one chemical 9h had exceptional antitumor efficacy. [ABSTRACT FROM AUTHOR]

In a binary liquid mixture containing pyrimidine-substituted azetidinone ultrasonic velocities, densities, and viscosities have been measured by unit of molality azetidinone at temperatures T = (298.15, 308.15, and 313.15 K). 3-chloro-4-(4-nitrophenyl)-1-(pyrimidin-2-yl)azetidin-2-one (AT1) and 3-chloro-4-(4-chlorophenyl)-1-(pyrimidin-2-yl)azetidin-2-one (AT2) in N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) were studied. The density, dynamic viscosity, and ultrasonic sound velocity have all been measured, among other acoustical and thermodynamic properties. Gibbs free energy of activation (ΔG*), enthalpy of activation (ΔH*), and entropy of activation (ΔS*) values have been studied further to determine how solvent changes and structural modifications impact these values. The molecular interactions between the components of the liquid combination have been used to explain these findings. [ABSTRACT FROM AUTHOR]

The design, synthesis, and biological screening of novel 4-aryl-6-[6-(2,4-dichlorophenyl)-2-methyl-pyridin-3-yl]-3,4-dihydropyrimidine-2(1H)-thiones and 2′-amino-6′-aryl-6-(2,4-dichlorophenyl)-2-methyl[3,4′-bipyridine]-3′-carbonitriles are described. The reaction involves Claisen–Schmidt condensation to afford the target compounds in up to 93% yield. The synthesized compounds were characterized by using FT-IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis and were screened for their antibacterial activity against both gram-negative and gram-positive bacterial strains. Methoxy-, hydroxy-, and halogen-substituted deriva-tives showed good inhibitory effect against the tested microorganisms. Also, some of the compounds showed better anti-inflammatory activity when compared to the standards. The electron-donor properties of the novel pyrimidine derivatives were confirmed by quantum chemical studies. [ABSTRACT FROM AUTHOR]

–Objective: In this paper, a series of piperazine pyrimidines and morpholine pyrimidines have been synthesized effectively, and their biological activities have been evaluated. Methods: We examined the cytotoxicity tests of the compounds against two human tumor cells (HCT-116, HeLa), as well as one human normal cells (L02), in order to determine their anticancer activity. Results: The compound (IV) outperformed the others, and flow cytometry was used to further examine how it works against cancer. Additionally, the (IV) molecule showed strong anticancer efficacy but was marginally less effective in apoptosis assays than the control 5-FU. Discussion: The compound (IV) chemical treated HCT-116 cells and HeLa cells in the cell cycle research had a larger percentage of cells in the G1 phase. The induction of apoptosis by interfering with the cell cycle may be the anticancer mechanism of this substance. Additionally, molecular docking investigated potential interactions between the substances and the Topo II active site. Conclusions: The groundwork for the creation and structural modification of new pyrimidine medications is laid out in this study. [ABSTRACT FROM AUTHOR]

Objective: To synthesize new dihydropyrazolo[1,5-a]pyrimidine derivatives and screen for the antibacterial and antifungal screening. Methods: We have synthesized a new series of 7-(1,3-diphenyl-1-H-pyrazol4-yl)-2-(methylthio)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile compounds and screened compounds for antibacterial and antifungal activity. Gram-positive (Bacillus megaterium, Micrococcus spp.) and Gram-negative bacteria were tested for antibacterial activity (E.coli, S. typhi). Antifungal activity was tested on Ganoderma spp., A. niger, A. flavus, and Penicillium spp.Results: Some compounds have shown significant antimicrobial activity. Discussion: As per the results the compound possesses good biological activity due to presence of core pyrazolo[1,5-a]pyrimidine moiety. Conclusions: The synthesis of new 7-(1,3-diphenyl-1-Hpyrazol-4-yl)-2-(methylthio)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile compounds was successfully completed and characterized by relevant techniques. Compounds are screened for the biological activities with moderate to good results. The MIC of the synthesized compound is compared to marketed available standard drugs. [ABSTRACT FROM AUTHOR]

A general strategy was developed for the synthesis of new fully decorated sulfonyl1,2,3-triazolyl pyrimidines (6a–6j and 8a–8f) from 2-((6-methyl-2-(methylsulfonyl)pyrimidin-4-yl)sulfonyl)-1-(4-nitrophenyl)ethanone and several azides in the presence of catalytic amounts of organocatalyst. Ramachary OrgAKC reaction of β-ketosulfone (4) acts as an internal alkyne as reported for the synthesis of sulfonyl-1,2,3-triazolyl pyrimidines at 80 °C in good to excellent yields of products in the presence of catalytic amounts of pyrrolidine (10 mol %). In vitro anticancer activity of all these derivatives revealed that six compounds like 6d, 6e, 6g, 6h, 8c, and 8d were active against three human cancer cell lines like breast carcinoma, cervical carcinoma, and alveolar carcinoma. In specific, compounds 6g and 6h showed superior activity against tested cell lines compared to the standard drug erlotinib. Later, the results of inhibitory assay of potent compounds 6d, 6e, 6g, 6h, 8c, and 8d against the tyrosine kinase epidermal growth factor receptor (EGFR) revealed that compounds 6g and 6h showed more potency than the reference drug erlotinib. [ABSTRACT FROM AUTHOR]

A new 5,6,7,8‐tetrahydroquinazoline (i. e. 1,3‐diazanaphthalene) scaffold with four points of diversification RA−RD was prepared. The sequence started from nitroalkanes RCCH2NO2 (with RC = Me, Bu), ethyl acrylate and amidines RAC(NH)NH2 (with RA = Ph, 4‐pyridyl) which were converted in a conjugate addition, Dieckmann condensation and pyrimidine ring formation. After transformation of the OH group in 4‐position to a chloro leaving group, residues RB were introduced by nucleophilic substitution with alkyl amines RBNH2 (10 examples) or aryl thiols RBSH (two examples). Finally, the nitro group in the 6‐position was reduced and the primary amino function amidated with various carboxylic acids RDCO2H. Along this seven‐step sequence, eight examples of the fully decorated scaffold were prepared. [ABSTRACT FROM AUTHOR]

Introduction: The anticancer and anti-inflammatory activities of a novel series of eleven pyrimido[1,2-b]pyridazin-2-one analogues substituted at position 7 were assessed in the current study. Methods: The physicochemical characteristics were studied using MolSoft software. The antiproliferative activity was investigated by MTT cell viability assay, and cell cycle analysis elucidated the antiproliferative mechanism of action. Western blot analysis examined the expression levels of key pro-apoptotic (Bax, p53) and pro-survival (Bcl-2) proteins. The anti-inflammatory activity was assessed by measuring the production levels of nitric oxide in RAW264.7 cells, and the expression levels of COX-2 enzyme in LPS-activated THP-1 cells. In addition, the gene expression of various pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNF-α) and chemokines (CCL2, CXCL1, CXCL2, CXCL3) was assessed by RT-qPCR. Results: Compound 1 bearing a chlorine substituent displayed the highest cytotoxic activity against HCT-116 and MCF-7 cancer cells where IC50 values of 49.35 ± 2.685 and 69.32 ± 3.186 µM, respectively, were achieved. Compound 1 increased the expression of pro-apoptotic proteins p53 and Bax while reducing the expression of pro-survival protein Bcl-2. Cell cycle analysis revealed that compound 1 arrested cell cycle at the G0/G1 phase. Anti-inflammatory assessments revealed that compound 1 displayed the strongest inhibitory activity on NO production with IC50 of 29.94 ± 2.24 µM, and down-regulated the expression of COX-2. Compound 1 also induced a statistically significant decrease in the gene expression of various cytokines and chemokines. Conclusion: These findings showed that the pyrimidine derivative 1 displayed potent anti-inflammatory and anticancer properties in vitro , and can be selected as a lead compound for further investigation. [ABSTRACT FROM AUTHOR]

In this work, a series of new diarylpyrimidine derivatives as microtubule destabilizers were designed, synthesized, and evaluated for anticancer activities. Based on restriction configuration strategy, we introduced the pyrimidine moiety containing the hydrogen-bond acceptors as cis-olefin bond of CA-4 analogs to improve structural stability. Compounds 11a-t exerted antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and MCF-7), due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HSF cells, as evidenced by MTT assays. In mechanistic investigations, compound 11s remarkably inhibited tubulin polymerization and disorganized microtubule in SGC-7901 cells by binding to tubulin. Moreover, 11s caused G2/M phase cell cycle arrest in SGC-7901 cells in a concentration-dependent manner. Furthermore, molecular modeling analysis revealed that 11s interacts with tubulin through binding to the colchicine site. In addition, the prediction of physicochemical properties disclosed that 11s conformed well to the Lipinski’s rule of five. This work offered a fresh viewpoint for the discovery of new tubulin-targeting anticancer drugs.

A new series of 1,2,3-triazole incorporated pyridin-4-yl)-1H-1,2,4-triazol-3-yl)pyrimidine (10a-j) has been synthesized and their structures were characterized by 1HNMR, 13CNMR and mass spectral data. The in vitro anticancer activity of these derivatives (10a-j) was evaluated against human cancer cell lines such as MCF-7 (human breast cancer), A549 (human lung cancer), Colo-205 (human colon cancer) and A2780 (human ovarian cancer) by employing the MTT method. The results were expressed as IC50 µM and most of the derivatives showed good to moderate activity as compared with etoposide which is used as a positive control. Among all the derivatives, six derivatives 10a, 10b, 10c, 10d, 10e and 10j showed more potent activity. Particularly, one compound 10a displayed the most promising activity.

Abstract Metabolic abnormalities contribute to the pathogenesis of obesity and its complications. Yet, the understanding of the interactions between critical metabolic pathways that underlie obesity remains to be improved, in part owing to the lack of comprehensive metabolomics studies that reconcile data from both hydrophilic and lipophilic metabolome analyses that can lead to the identification and characterization of key signaling networks. Here, the study conducts a comprehensive metabolomics analysis, surveying lipids and hydrophilic metabolites of the plasma and omental adipose tissue of obese individuals and the plasma and epididymal adipose tissue of mice. Through these approaches, it is found that a significant accumulation of ceramide due to inhibited sphingolipid catabolism, while a significant reduction in the levels of uridine monophosphate (UMP), is critical to pyrimidine biosynthesis. Further, it is found that UMP administration restores sphingolipid homeostasis and can reduce obesity in mice by reversing obesity‐induced inhibition of adipocyte hypoxia inducible factor 2a (Hif2α) and its target gene alkaline ceramidase 2 (Acer2), so as to promote ceramide catabolism and alleviate its accumulation within cells. Using adipose tissue Hif2α‐specific knockout mice, the study further demonstrates that the presence of UMP can alleviate obesity through a HIF2α‐ACER2‐ceramide pathway, which can be a new signaling axis for obesity improvement.

In diseases like atherosclerosis, rheumatoid arthritis, and sepsis, phospholipase A2 (PLA2) and proteinase K play a role in inflammation by releasing arachidonic acid (AA). The crucial step in the inflammatory process is believed to be the release of prostaglandins after PLA2 mobilizes AA. Drugs obstructing the COX and LOX pathways in the arachidonic acid cascade, drugs that inhibit these enzymes can treat inflammatory processes. To combat against these inflammatory promoters,the authors herein report an effective method for the synthesis of a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (4a–h) under the effect of TiO2 as a photocatalyst in ethanolic medium, and their effect against phospholipase A2, as well as proteinase K, was evaluated. The results confirmed that using TiO2 (20 mg) as a photocatalyst exhibits excellent performance in terms of yield and reaction time. The yield of all the synthesized compounds is between 79 and 91 % in just 60 min. After closely evaluating the SAR of the examined compounds against both enzymes, it was discovered that compounds (4b, 4f) with electron-donating substituents have higher PLA2 inhibitory (%) activity than those with electron-removing substituents (4a, 4e). Compounds (4c, 4d) containing heterocyclic rings showed significantly higher proteinase inhibitory (%) activity when compared to other electron-donating or withdrawing compounds. It was further confirmed that studied compounds against both enzymes exhibited dose-dependent behavior. We studied the intermolecular interactions of the compounds by molecular docking with human non-pancreatic secretory phospholipase A2 and proteinase K. We evaluated the dynamical stability of the docked complexes using a 100 ns molecular dynamics simulation, which revealed stable interactions based on root mean square deviation/fluctuation (RMSD/RMSF), radius of gyration, Gibbs free energy landscapes, and principal component analyses (PCA). Moreover, the ADME properties of the compounds align with Lipinski’s rule of five, suggesting their potential as viable candidates for the development of therapies against inflammatory diseases. All compounds tested inhibited PLA2 more than proteinase K. However, compounds 4b and 4f better inhibited phospholipase A2, whereas compounds 4c and 4d showed better activity against proteinase K.