Search Results (20)

Chalcopyrite and molybdenite are vital strategic metal resources. Due to their close association in ores, flotation methods are commonly used for separation. The flotation separation method primarily employs the “copper depression and molybdenum flotation” process, enhancing the wettability difference between chalcopyrite and molybdenite through a chalcopyrite depressant. Traditional depressants often face challenges, including low selectivity, high dosage requirements, poor stability, and significant environmental pollution, highlighting the need for new, highly selective green reagents. This study introduces the novel chalcopyrite depressant 2-mercapto-6-methylpyrimidin-4-ol (MMO) for flotation separation. The influence of MMO on chalcopyrite and molybdenite flotation recovery was examined through microflotation experiments. Additionally, the effects of MMO and ethyl xanthate on surface wettability were assessed via contact angle measurements. The adsorption microstructure and interaction mechanism of MMO on chalcopyrite were elucidated using FT-IR, TOF-SIMS, and XPS analyses and DFT simulations. Results indicate that MMO enhances chalcopyrite hydrophilicity and exhibits a strong depressing effect on its flotation, while minimally impacting molybdenite recovery. Thus, it serves as an effective depressant. During adsorption, N and S atoms in MMO donate electrons to Fe and Cu ions, leading to triple bond adsorption and a stable chelate structure. These findings are crucial for achieving a greener and more efficient flotation separation of copper and molybdenum. Full article

This study aims to design improved inhibitors targeting the thymidylate kinase (TMK) of Mycobacterium tuberculosis (Mtb), the causative agent of infectious disease tuberculosis that is associated with high morbidity and mortality in developing countries. TMK is an essential enzyme for the synthesis of bacterial DNA. We have performed computer-aided molecular design of MtbTMK inhibitors by modification of the reference crystal structures of the lead micromolar inhibitor TKI1 1-(1-((4-(3-Chlorophenoxy)quinolin-2-yl)methyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione bound to TMK of Mtb strain H37Rv (PDB entries: 5NRN and 5NR7) using the computational approach MM-PBSA. A QSAR model was prepared for a training set of 31 MtbTMK inhibitors with published inhibitory potencies (${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$) and showed a significant correlation between the calculated relative Gibbs free energies of the MtbTMK–TKIx complex formation and the observed potencies. This model was able to explain approximately 95% of the variation in the in vitro inhibition data and validated our molecular model of MtbTMK inhibition for the subsequent design of new TKI analogs. Furthermore, we have confirmed the predictive capacity of this complexation QSAR model by generating a 3D QSAR PH4 pharmacophore-based model. A satisfactory correlation was also obtained for the validation PH4 model of MtbTMK inhibition (R² = 0.84). We have extended the hydrophobic m-chloro-phenoxyquinolin-2-yl group of TKI1 that can occupy the entry into the thymidine binding cleft of MtbTMK by alternative larger hydrophobic groups. Analysis of residue interactions at the enzyme binding site made it possible to select suitable building blocks to be used in the preparation of a virtual combinatorial library of 28,900 analogs of TKI1. Structural information derived from the complexation model and the PH4 pharmacophore guided the in silico screening of the library of analogs and led to the identification of new potential MtbTMK inhibitors that were predicted to be effective in the low nanomolar concentration range. The QSAR complexation model predicted an inhibitory concentration ${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ of 9.5 nM for the best new virtual inhibitor candidate TKI 13_1, which represents a significant improvement in estimated inhibitory potency compared to TKI1. Finally, the stability of the MtbTMK–inhibitor complexes and the flexibility of the active conformation of the inhibitors were assessed by molecular dynamics for five top-ranking analogs. This computational study resulted in the discovery of new MtbTMK inhibitors with predicted enhanced inhibitory potencies, which also showed favorable predicted pharmacokinetic profiles. Full article

In the course of this work, we explored the influence of the conditions of the Vilsmeier–Haack reaction for 2-methylpyrimidine-4,6-diol (1). We conducted a comparative analysis of approaches using various solvents (o-xylene, N,N-dimethylformamide (DMF), benzene, and dichloroethane) as the reaction medium, and the optimal one was selected. During the formylation of substrate 1 in these conditions, only 4,6-dihydroxy-2-methylpyrimidine-5-carbaldehyde (2) was successful. It should be noted that there was no substitution of hydroxyl groups for chlorine atoms observed in reactions with similar substrates. The structure of the resulting product 2 was proven using NMR spectroscopy on ¹H and ¹³C nuclei and by mass spectrometry. Full article

1,2,3-triazole pharmacophore is a widely recognized motif used for a variety of applications, including drug discovery, chemical biology, and materials science. We herein report the synthesis of a derivative of azidothymidine (AZT), which was combined with the 7-chloro quinoline scaffold through a 1,4-disubstituted 1,2,3-triazole. The chemical structure of the new molecule was fully characterized by Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (¹H-NMR), carbon-13 nuclear magnetic resonance (¹³C-NMR), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC) distortionless enhancement by polarization transfer (DEPT), correlation spectroscopy (¹H-¹H-COSY), ultraviolet (UV) spectroscopy, and high-resolution mass spectrometry (HRMS). Computational studies were used to predict the interaction of the synthesized compound with HIV reverse transcriptase, a target of relevance for developing new therapeutics against AIDS. The drug-likeness of the compound was also investigated by computing the physico-chemical properties that are important for the pharmacokinetic profile. Full article

A method for the technically easy-to-implement synthesis of deuterium-labeled pyrazolo[1,5-a]pyrimidines and 1,2,4-triazolo[1,5-a]pyrimidines have been developed. The regioselectivity of such transformations has been shown. ¹H NMR and mass spectrometric methods have proved the quantitative nature of such transformations and the kinetics of deuterium exchange has been studied. Spectrally, at different temperatures (+30 °C, −10 °C and −15 °C), the kinetics of the process was studied both in CD₃OD and in deuterated alkali. Full article

Cystathionine β-synthase (CBS), CSE (cystathionine γ-lyase) and 3-mercaptopyruvate sulfurtransferase (3-MST) have emerged as three significant sources of hydrogen sulfide (H₂S) in various forms of mammalian cancer. Here, we investigated the functional role of CBS’ and 3-MST’s catalytic activity in the murine breast cancer cell line EO771. The CBS/CSE inhibitor aminooxyacetic acid (AOAA) and the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) were used to assess the role of endogenous H₂S in the modulation of breast cancer cell proliferation, migration, bioenergetics and viability in vitro. Methods included measurements of cell viability (MTT and LDH assays), cell proliferation and in vitro wound healing (IncuCyte) and cellular bioenergetics (Seahorse extracellular flux analysis). CBS and 3-MST, as well as expression were detected by Western blotting; H₂S production was measured by the fluorescent dye AzMC. The results show that EO771 cells express CBS, CSE and 3-MST protein, as well as several enzymes involved in H₂S degradation (SQR, TST, and ETHE1). Pharmacological inhibition of CBS or 3-MST inhibited H₂S production, suppressed cellular bioenergetics and attenuated cell proliferation. Cell migration was only inhibited by the 3-MST inhibitor, but not the CBS/CSE inhibitor. Inhibition of CBS/CSE of 3-MST did not significantly affect basal cell viability; inhibition of 3-MST (but not of CBS/CSE) slightly enhanced the cytotoxic effects of oxidative stress (hydrogen peroxide challenge). From these findings, we conclude that endogenous H₂S, generated by 3-MST and to a lower degree by CBS/CSE, significantly contributes to the maintenance of bioenergetics, proliferation and migration in murine breast cancer cells and may also exert a minor role as a cytoprotectant. Full article

In the present work, complexes of cobalt(II), copper(II), and zinc(II), 2-amino-4-methylpyrimidineand, and 2,3-diaminopyridine were successfully prepared and characterized using elemental analysis, UV-visible, and FTIR spectroscopy, as well as magnetic susceptibility measurements, molar conductance, TGA analysis, and X-ray diffraction. From elemental and spectral data, the formulae [M(L1)(L2)Cl₂(H₂O)] (where L1 = AMPY (2-amino-4-methylpyrimidine) and L2 = DAPY(2,3-diaminopyridine)) and M = Co(II) (2), Cu(II) (2), and Zn(II)) for the metal complexes have been proposed. The geometric structures of the mixed-ligand complexes were found to be octahedral around the metal ions, and the XRD patterns showed monoclinic crystal systems with space group P2₁. The mode of bonding was pentacoordinate for Cu and hexacoordinate for Zn and Co. Different features may result from the fact that not all molecules have the same electron distribution. For example, Zn and Co have larger electron densities in at least one of the chlorides in the HOMO compared with pentacoordinate Cu, which has a small electron distribution on the chloride. Thermal analysis indicated that all metal complexes are stable up to about 88 °C with thermodynamically favored overlapped chemical reactions. Excellent antibacterial and antifungal activity was shown by the three synthesized forms of the complexes. The Zn(II) complex had a high level of antioxidant activity with a DPPH scavenging of 91.5%, whereas the Cu(II) complex had a low level of antioxidant potential (16.5%). The docking tests also showed that all compounds had good binding energy levels (7.2–7.9 kcal mol⁻¹). For this reason, all molecules can easily fit in the receptor protein’s catalytic sites. However, the Co(II) complex is shown to be more active. Full article

Uterine contractions prior to 37 weeks gestation can result in preterm labor with significant risk to the infant. Current tocolytic therapies aimed at suppressing premature uterine contractions are largely ineffective and cause serious side effects. Calcium (Ca²⁺) dependent contractions of uterine smooth muscle are physiologically limited by the opening of membrane potassium (K⁺) channels. Exploiting such inherent negative feedback mechanisms may offer new strategies to delay labor and reduce risk. Positive modulation of small conductance Ca²⁺-activated K⁺ (K_Ca2.3) channels with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), effectively decreases uterine contractions. This study investigates whether the receptor agonist oxytocin might solicit K_Ca2.3 channel feedback that facilitates CyPPA suppression of uterine contractions. Using isometric force myography, we found that spontaneous phasic contractions of myometrial tissue from nonpregnant mice were suppressed by CyPPA and, in the presence of CyPPA, oxytocin failed to augment contractions. In tissues exposed to oxytocin, depletion of internal Ca²⁺ stores with cyclopiazonic acid (CPA) impaired CyPPA relaxation, whereas blockade of nonselective cation channels (NSCC) using gadolinium (Gd³⁺) had no significant effect. Immunofluorescence revealed close proximity of K_Ca2.3 channels and ER inositol trisphosphate receptors (IP₃Rs) within myometrial smooth muscle cells. The findings suggest internal Ca²⁺ stores play a role in K_Ca2.3-dependent feedback control of uterine contraction and offer new insights for tocolytic therapies. Full article

Two new complexes, [Cu(dimpyr)₂(H₂O)₂](NO₃)₂.2H₂O (1) and (Hamdimpy)₂[CoCl₄].H₂O (2), with the monodentate ligand 2-amino-6-methylpyrimidin-4-(1H)-one (dimpyr) and the countercation 4-amino-2,6-dimetylpyrimidium (Hamdimpy), respectively, were prepared and characterized by single crystal X-ray diffraction, elemental analysis and IR spectroscopy. In (1), the Cu(II) cation is tetracoordinated, in a square plan fashion, by two nitrogen atoms from the pyrimidine ring of the organic ligand and two oxygen atoms of two coordinated water molecules. In the atomic arrangement, the CuO₂N₂ square planes are interconnected via the formation of O-H…O hydrogen bonds involving both coordinated and free water molecules and NO₃⁻ nitrate anions to form inorganic layers parallel to the (a, b) plane at z = (2n + 1)/4. In (2), the central atom Co(II) is four-coordinated in a distorted tetrahedral fashion by four Cl⁻ ions. The [CoCl₄]²⁻ tetrahedra are arranged parallel to the plane ($\overline{1}$10) at x = (2n + 1)/2 and the organic cations are grafted between them by establishing with them hydrogen bonds of CH…Cl and NH…Cl types. The vibrational absorption bands were identified by infrared and Raman spectroscopy. Intermolecular interactions were investigated via Hirshfeld surfaces and electronic properties such as HOMO and LUMO energies were derived. The two compounds were characterized by thermal analysis to determine their thermal behavior with respect to temperature. Full article

MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [³H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [³H]TH287 has a dissociation constant (K_d) of 1.97 ± 0.18 nM, B_max of 2676 ± 122 fmol/mg protein for U251MG cells, and n_H of 0.98 ± 0.02. Competitive binding assays show that TH287 (K_i: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (K_i: 153.90 ± 20.48 nM). In vitro enzymatic assays show that TH287 has an IC₅₀ of 2.2 nM in inhibiting MTH1 hydrolase activity and a K_i of 1.3 nM from kinetics assays, these results are consistent with our radioligand binding assays. Furthermore, MicroPET imaging shows that [¹¹C]TH287 gets into the brain with rapid clearance from the brain, kidney, and heart. The results presented here indicate that radiolabeled TH287 has favorable properties to be a useful tool for measuring MTH1 in vitro and for further evaluation for in vivo PET imaging MTH1 of brain tumors and other central nervous system disorders. Full article

Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity. Full article

We investigated whether the substrate for nitric oxide (NO) production, extracellular l-arginine, contributes to relaxations induced by activating small (SKCa) conductance Ca²⁺-activated potassium channels. In endothelial cells, acetylcholine increased ³H-l-arginine uptake, while blocking the SKCa and the intermediate (IKCa) conductance Ca²⁺-activated potassium channels reduced l-arginine uptake. A blocker of the y+ transporter system, l-lysine also blocked ³H-l-arginine uptake. Immunostaining showed co-localization of endothelial NO synthase (eNOS), SKCa3, and the cationic amino acid transporter (CAT-1) protein of the y+ transporter system in the endothelium. An opener of SKCa channels, cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) induced large currents in endothelial cells, and concentration-dependently relaxed porcine retinal arterioles. In the presence of l-arginine, concentration-response curves for CyPPA were leftward shifted, an effect unaltered in the presence of low sodium, but blocked by l-lysine in the retinal arterioles. Our findings suggest that SKCa channel activity regulates l-arginine uptake through the y+ transporter system, and we propose that in vasculature affected by endothelial dysfunction, l-arginine administration requires the targeting of additional mechanisms such as SKCa channels to restore endothelium-dependent vasodilatation. Full article

Metal-organic complex exhibiting spin crossover (SCO) behavior has drawn attention for its functionality as a nanoscale spin switch. The spin states in the metal ions can be tuned by external stimuli such as temperature or light. This article demonstrates a soft X-ray–induced excited spin state trapping (SOXEISST) effect in Hofmann-like SCO coordination polymers of Fe^II(4-methylpyrimidine)₂[Au(CN)₂]₂ and Fe^II(pyridine)₂[Ni(CN)₄]. A soft X-ray absorption spectroscopy (XAS) study on these polymers showed that the high spin configuration (HS; S = 2) was prevalent in Fe²⁺ ions during the measurement even at temperatures much lower than the critical temperatures (>170 K), manifesting HS trapping due to the X-ray irradiation. This is in strong contrast to the normal SCO behavior observed in Fe^II(1,10-phenanthroline)₂(NCS)₂, implying that the structure of the ligand chains in the polymers with relatively loose Fe-N coordination might allow a structural adaptation to stabilize the metastable HS state under the soft X-ray irradiation. Full article

There are several challenges involved in the development of effective anti-cancer drugs, including accurate drug delivery without toxic side effects. Possible systemic toxicity and the rapid biodegradation of drug carriers are potential risks in the use of carriers for drug-delivery formulations. Therefore, the carrier-free drug delivery of an anti-cancer drug is desirable. Herein, 4-amino-2-benzyl-6-methylpyrimidine (ABMP) was synthesized via a new method using a sodium catalyst, and proved to be effective in inducing breast cancer cell (MDA-MB-231) apoptosis. Moreover, the transparent amorphous state solid of ABMP was demonstrated to have a slow-release property in phosphate buffer solution (PBS). Microspheres of ABMP were prepared with diameters in the range of 5–15 μm. The slow-release property of the ABMP microspheres indicated their potential use for controlled-release drug delivery. We believe that microspheres of ABMP have potential as a new kind of carrier-free anti-cancer drug delivery system. Full article

A comparative investigation of the coordination assemblies formed between Co(NCS)₂ and two monotopic 4,2’:6’,4’’-terpyridine (4,2’:6’,4”-tpy) ligands or two related ditopic ligands is reported. Crystals were grown by layering MeOH solutions of Co(NCS)₂ over a CHCl₃ or 1,2-C₆H₄Cl₂ solution of the respective ligand at room temperature. With 4’-(2-methylpyrimidin-5-yl)-4,2’:6’,4”-terpyridine (6), the 1D-coordination polymer {[Co₂(NCS)₄(MeOH)₄(6)₂]∙2MeOH∙8H₂O}_n assembles with 6 coordinating only through the outer N-donors of the 4,2’:6’,4”-tpy unit; coordination by the MeOH solvent blocks two cobalt coordination sites preventing propagation in a higher-dimensional network. A combination of Co(NCS)₂ and 1-(4,2‘:6’,4”-terpyridin-4’-yl)ferrocene (7) leads to {[Co(NCS)₂(7)₂]∙4CHCl₃}_n which contains a (4,4) net; the 2D-sheets associate through π-stacking interactions between ferrocenyl and pyridyl units. A 3D-framework is achieved through use of the ditopic ligand 1,4-bis(ⁿpropoxy)-2,5-bis(4,2’:6’,4”-terpyridin-4’-yl)benzene (8) which acts as a 4-connecting node in {[Co(NCS)₂(8)₂]^.2C₆H₄Cl₂}_n; the combination of metal and ligand planar 4-connecting nodes results in a {6⁵.8} cds net. For a comparison with the coordinating abilities of the previously reported 1,4-bis(ⁿoctoxy)-2,5-bis(4,2’:6’,4”-terpyridin-4’-yl)benzene (3), a more flexible analogue 9 was prepared. {[Co(NCS)₂(9)]∙2CHCl₃}_n contains a (4,4) net defined by both metal and ligand planar 4-connecting nodes. The ⁿoctoxy tails of 9 protrude from each side of the (4,4) net and thread through adjacent sheets; the arene-attached ⁿoctoxy chains associate through a combination of van der Waals and C–H...π interactions. Full article