Search Results (29)

The pyrrolo[2,3-d]pyrimidine (7-deazapurine) scaffold is a unique heterocyclic system included in the composition of most nucleotides. In this study, series of the pyrrolo[2,3-d]pyrimidine-imines and 3-halo-substituted pyrrolo[2,3-d]pyrimidines were designed and prepared in high yields. Condensed pyrimidines are obtained via carbonyl-amine condensation and carbon-halogen bond formation. Pyrrolo[2,3-d]pyrimidine-imines containing a bromine substituent at position C-4 of the phenyl ring and azepine side-ring exhibited superior antitumor activity on the colon cancer HT-29 cell line; IC₅₀ values were 4.55 and 4.01 µM, respectively. These results revealed an interesting pattern, where condensed pyrimidinones containing an azepine ring demonstrated selective antitumor activity on the colon cancer cell line HT-29. In addition, the molecular docking results suggest that compound 8g provided a thorough understanding of its interactions with the DDR2 active site. This could pave the way for further development and optimization of DDR-targeting drugs, contributing to advancements in cancer therapeutics. This lead compound may serve as design templates for further studies. Full article

Background/objectives: Brain cancer remains difficult to treat, with survival statistics stagnant for decades. The resistance of glioblastoma brain tumours can greatly challenge the effectiveness of conventional cancer radiotherapy. However, high dose rate radiotherapy has unique effects that allow for normal tissue sparing whilst maintaining tumour control. The addition of targeted radiosensitisers, such as the chemotherapeutic drug methotrexate (MTX) or the high-Z halogenated pyrimidine drug iododeoxyuridine (IUdR), can improve radiotherapy outcomes. Combining these radiosensitiser agents with ultra-high dose rate (UHDR) synchrotron X-rays can bear synergistic effects to enhance the efficacy of these multi-modal UHDR therapies, providing a means to overcome the radioresistance of brain cancer. Methods: Here, we use controlled in vitro assays following treatment, including a clonogenic assay to determine long-term cell survival and γH2AX immunofluorescent confocal microscopy to quantify double-strand DNA breaks (DSBs). Results: We find significant enhancement for highly synergistic combinations of IUdR+MTX with synchrotron X-rays. Cell survival results demonstrate 5.4 times increased 9L gliosarcoma cell killing when these agents are combined with UHDR synchrotron X-rays compared with conventional X-rays alone at the same 5 Gy dose. The underlying mechanisms are unveiled using γH2AX imaging and reveal significant increases in DSBs and dying cells following exposure to UHDR radiation. Conclusions: Our results demonstrate that highly synergistic combination treatments using UHDR synchrotron radiation can yield significantly improved brain cancer killing compared with conventional radiotherapy. We anticipate that these additive, multi-modal combination therapies will provide options for more targeted and effective use of radiotherapies for the future treatment of brain cancer. Full article

Enterohemorrhagic Escherichia coli (EHEC) is a significant public health concern due to its ability to form biofilms, enhancing its resistance to antimicrobials and contributing to its persistence in food processing environments. Traditional antibiotics often fail to target these biofilms effectively, leading to increased bacterial resistance. This study aims to explore the efficacy of novel antibiofilm agents, specifically halogenated pyrimidine derivatives, against EHEC. We screened pyrimidine and 31 halogenated pyrimidine derivatives for their antimicrobial and antibiofilm activities against EHEC using biofilm quantification assays, SEM analysis, motility, and curli production assessments. Our findings reveal that certain halogenated pyrimidine derivatives, notably 2-amino-5-bromopyrimidine (2A5BP), 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (2A4CPP), and 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2,4DC5IPP) at 50 µg/mL, exhibited significant inhibitory effects on EHEC biofilm formation without affecting bacterial growth, suggesting a targeted antibiofilm action. These compounds effectively reduced curli production and EHEC motility, essential factors for biofilm integrity and development. qRT-PCR analysis revealed that two active compounds downregulated the expression of key curli genes (csgA and csgB), leading to reduced bacterial adhesion and biofilm formation. Additionally, in silico ADME–Tox profiles indicated that these compounds exhibit favorable drug-like properties and lower toxicity compared with traditional pyrimidine. This study highlights the potential of halogenated pyrimidine derivatives as effective antibiofilm agents against EHEC, offering a promising strategy for enhancing food safety and controlling EHEC infections. The distinct mechanisms of action of these compounds, particularly in inhibiting biofilm formation and virulence factors without promoting bacterial resistance, underscore their therapeutic potential. Full article

The total cross-sections for the single electron-impact ionization of pyrimidine (C₄H₄N₂), 2-chloropyrimidine (2-C₄H₃ClN₂), 5-chloropyrimidine (5-C₄H₃ClN₂), 2-bromopyrimidine (2-C₄H₃BrN₂) and 5-bromopyrimidine (5-C₄H₃BrN₂) molecules have been calculated with the binary-encounter-Bethe model from the ionization threshold up to 5 keV. The input data for the BEB calculations concerning electronic structure of the studied targets have been obtained with quantum chemical methods including the Hartree–Fock (H-F) and the outer valence Green function (OVGF) methods. The calculated cross-section for the ionization of the pyrimidine molecules due to electron impact is compared with available experimental and theoretical data. The question of the magnitude the pyrimidine ionization cross-section is also discussed, as is the efficiency of the ionization process of studied halogenated derivatives of pyrimidine. Full article

Background/Objectives: Brain cancer is notoriously resistant to traditional treatments, including radiotherapy. Microbeam radiation therapy (MRT), arrays of ultra-fast synchrotron X-ray beams tens of micrometres wide (called peaks) and spaced hundreds of micrometres apart (valleys), is an effective alternative to conventional treatments. MRT’s advantage is that normal tissues can be spared from harm whilst maintaining tumour control. Combining MRT with targeted radiosensitisers, such as nanoparticles, chemotherapeutic drugs, and halogenated pyrimidine drugs, can further improve radiotherapy by enhancing radiation damage. However, the underlying mechanisms of MRT are still being understood, which is essential to ensuring the reliable and successful use of MRT. Methods: An in vitro study was performed using γH2AX imaging, and quantification was performed via confocal microscopy and a clonogenic cell survival assay. Results: We show that methotrexate chemotherapeutics and iododeoxyuridine enhance MRT cell-killing and thulium oxide nanoparticles (TmNPs) broaden MRT peaks, and using γH2AX immunofluorescent confocal microscopy to quantify DNA damage, we further our knowledge of MRT mechanisms. γH2AX images verify the biological responses of cells aligning with the physical collimation of MRT, and we can accurately measure MRT microbeam characteristics bio-dosimetrically. The peak-to-valley dose ratio (PVDR), the ratio of the peak dose to the valley dose that characterises an MRT field, was accurately measured biologically using γH2AX imaging, despite studies previously finding this challenging. Conclusions: The measurement of biological PVDR has been performed for the first time with high-Z radiosensitisers, including nanoparticles, and several novel radiosensitiser-enhanced MRT mechanisms were discovered. Our results deepen our understanding of MRT with radiosensitisers, and can contribute to its accurate and future successful use in treating cancer. Full article

Staphylococcus aureus, prevalent in hospital and community settings, forms biofilms that are highly resistant to antibiotics and immune responses, complicating treatment and contributing to chronic infections. These challenges underscore the need for novel treatments that target biofilm formation and effectively reduce bacterial virulence. This study investigates the antibiofilm and antimicrobial efficacy of novel halogenated pyrimidine derivatives against S. aureus, focusing on three compounds identified as potent biofilm inhibitors: 2,4-dichloro-5-fluoropyrimidine (24DC5FP), 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (24DC5BPP), and 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (24DC5IPP). The three active compounds are bacteriostatic. In particular, 24DC5FP at 5 µg/mL achieved a 95% reduction in hemolysis with a minimum inhibitory concentration (MIC) of 50 µg/mL. Interestingly, 24DC5FP increased cell size and produced wrinkled colonies. qRT-PCR analysis showed that 24DC5FP suppressed the gene expressions of agrA and RNAIII (quorum sensing regulator and effector), hla (α-hemolysin), nuc1 (nucleases nuc1), and saeR (S. aureus virulence regulator). These findings suggest that extensive halogenation enhances the antibiofilm and antivirulence activities of pyrimidine derivatives, offering a promising strategy for combatting S. aureus infections, including those resistant to conventional treatments. Full article

This work is devoted to the synthesis of triazolyl derivatives based on propargyl ethers of the thiazolo[3,2-a]pyrimidine series by [3+2]-cycloaddition and the study of their structure in solution and crystalline phase. The formation of homochiral chains in the crystalline phase is attributed to the establishment of a halogen bond between the bromine atom and the nitrogen atom of the nitrile group. Additionally, the generation of a racemic dimer is linked to the formation of a halogen bond between the bromine atom and the nitrogen atom of the triazolyl fragment. Full article

In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(E)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely 5e, 5h, 5k, and 5l, promising cytotoxic effects were observed against four different cancer cell lines, with IC₅₀ values ranging from 29 to 59 µM. Notably, compound 5k emerged as the most potent inhibitor, exhibiting significant activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC₅₀ values ranging from 40 to 204 nM, comparable to the well-known TKI sunitinib (IC₅₀ = 261 nM). Mechanistic investigations of compound 5k revealed its ability to induce cell cycle arrest and apoptosis in HepG2 cells, accompanied by a notable increase in proapoptotic proteins caspase-3 and Bax, as well as the downregulation of Bcl-2 activity. Furthermore, molecular docking studies indicated similar binding interactions between compound 5k and the four enzymes, as observed with sunitinib. These findings highlight the potential of compound 5k as a promising candidate for further development as a multi-targeted kinase inhibitor with enhanced potency. Full article

The isosteric replacement of the benzene with thiophene ring is a chemical modification widely applied in medicinal chemistry. Several drugs containing the thiophene ring are marketed for treating various pathologies (osteoporosis, peripheral artery disorder, psychosis, anxiety and convulsion). Taking into account this evidence and as a continuation of our study in the GABA_A receptor modulators field, we designed and synthesized new compounds containing the thiophene ring with 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidine and pyrazolo[1,5-a]thieno[2,3-c] pyrimidine scaffold. Moreover, these cores, never reported in the literature, are isosteres of pyrazolo[1,5-a]quinazolines (PQ), previously published by us as GABA_AR subtype ligands. We introduced in the new scaffold those functions and groups (esters, ketones, alpha/beta-thiophene) that in our PQ derivatives were responsible for the activity, and at the same time, we have extensively investigated the reactivity of the new nucleus regarding the alkylation, reduction, halogenation and hydrolyses. On the six final designed compounds (12c–f, 22a,b) molecular docking and dynamic simulation studies have been performed. The analysis of dynamic simulation, applying our reported model ‘Proximity Frequencies’, collocates with high probability 12c, 22b, in the agonist class towards α1β2γ2-GABA_AR. Full article

Nucleoside analogues are important compounds for the treatment of viral infections or cancers. While (chemo-)enzymatic synthesis is a valuable alternative to traditional chemical methods, the feasibility of such processes is lowered by the high production cost of the biocatalyst. As continuous enzyme membrane reactors (EMR) allow the use of biocatalysts until their full inactivation, they offer a valuable alternative to batch enzymatic reactions with freely dissolved enzymes. In EMRs, the enzymes are retained in the reactor by a suitable membrane. Immobilization on carrier materials, and the associated losses in enzyme activity, can thus be avoided. Therefore, we validated the applicability of EMRs for the synthesis of natural and dihalogenated nucleosides, using one-pot transglycosylation reactions. Over a period of 55 days, 2′-deoxyadenosine was produced continuously, with a product yield >90%. The dihalogenated nucleoside analogues 2,6-dichloropurine-2′-deoxyribonucleoside and 6-chloro-2-fluoro-2′-deoxyribonucleoside were also produced, with high conversion, but for shorter operation times, of 14 and 5.5 days, respectively. The EMR performed with specific productivities comparable to batch reactions. However, in the EMR, 220, 40, and 9 times more product per enzymatic unit was produced, for 2′-deoxyadenosine, 2,6-dichloropurine-2′-deoxyribonucleoside, and 6-chloro-2-fluoro-2′-deoxyribonucleoside, respectively. The application of the EMR using freely dissolved enzymes, facilitates a continuous process with integrated biocatalyst separation, which reduces the overall cost of the biocatalyst and enhances the downstream processing of nucleoside production. Full article

Thiazolopyrimidines are attractive to medical chemists as new antitumor agents due to their high inhibitory activity against the replication process of tumor cells and the easy modification of their structure by changing the number and nature of substituents. The presence of asymmetric C5 carbon atoms requires the development of racemic mixture separation procedures for these heterocycles. One of the most effective methods is the crystallization of a racemic compound in the form of a conglomerate. The prerequisite for such separation is the construction of chiral, supramolecular ensembles in the crystalline state. Halogen-π interactions were chosen as supramolecular synthons. In this context, ethyl 7-methyl-3-oxo-2,3-dihidro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate containing a 4-bromophenyl fragment at C5 was synthesized. The crystal structure of the resulting compound was established using SCXRD. The role of the halogen-π interaction on the formation of one-dimensional homochiral chains is revealed. Full article

A series of new 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with different aryl substituents at the 5 position are synthesized and characterized by ¹H/ ¹³C NMR and IR-spectroscopy and mass-spectrometry, as well as single crystal X-ray diffraction (SCXRD). It was demonstrated that the type of hydrogen bonding can play a key role in the chiral discrimination of these compounds in the crystalline phase. The hydrogen bond of the O–H...N type leads to 1D supramolecular heterochiral chains or conglomerate crystallization in the case of the formation of homochiral chains. The hydrogen bond of O–H...O type gave racemic dimers, which are packed into 2D supramolecular layers with a parallel or angular dimers arrangement. Halogen bonding of the N...Br or O...Br type brings a new motif into supramolecular self-assembly in the crystalline phase: the formation of 1D supramolecular homochiral chains instead 2D supramolecular layers. The study of cytotoxicity against various tumor cells in vitro was carried out. It was found that 2-hydroxy−3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with 3-nitrophenyl substituent at C5 carbon atom demonstrated a high efficiency against M-HeLa (cervical adenocarcinoma) and low cytotoxicity against normal liver cells. Full article

The overexpression of p21-activated kinase 4 (PAK4) is associated with a variety of cancers. In this paper, the binding modes and inhibitory mechanisms of four 7H-pyrrolo[2,3-d]pyrimidine competitive inhibitors of PAK4 were investigated at the molecular level, mainly using molecular dynamics simulations and binding free energy calculations. The results show that the inhibitors had strong interactions with the hinge region, the β-sheets, and the residues with charged side chains around the 4-substituent. The terminal amino group of the inhibitor 5n was different from the other three, which could cause the enhancement of hydrogen bonds or electrostatic interactions formed with the surrounding residues. Thus, inhibitor 5n had the strongest inhibition capacity. The different halogen atoms on the 2-substituents of the inhibitors 5h, 5g, and 5e caused differences in the positions of the 2-benzene rings and affected the interactions of the hinge region. It also affected to some extent the orientations of the 4-imino groups and consequently their affinities for the surrounding charged residues. The combined results lead to the weakest inhibitory capacity of inhibitor 5e. Full article

In this work, O- and N-N-bridging complexes of technetium (V), previously known only for rhenium, were obtained for the first time. Tc(V) complexes with pyridazine (pyd), 1,2,4-triazole (trz), 3,5-dimethylpyrazole (dmpz) and pyrimidine (pyr) were obtained. In three complexes [{TcOCl₂}₂(μ-O)(μ-pyd)₂], [{TcOCl₂}₂(μ-O)(μ-trz)₂]·Htrz·Cl and [{TcO(dmpz)₄}(μ-O)(TcOCl₄)] two technetium atoms are linked by a Tc-O-Tc bond, and in the first two, Tc atoms are additionally linked by a Tc-N-N-Tc bond through the nitrogen atoms of the aromatic rings. We determined the role of nitrogen atom position in the aromatic ring and the presence of substituents on the formation of such complexes. For the first time, a reaction mechanism for the formation of such complexes was proposed. This article details the crystal structures of four new compounds. The work describes in detail the coordination of Tc atoms in the obtained structures and the regularities of the formation of crystal packings. The spectroscopic properties of the obtained compounds and their mother solutions were studied. The decomposition temperatures of the described complexes were determined. An assumption was made about the oligomerization of three-bridged complexes based on the results of mass spectrometry. Through the analysis of non-valent interactions in the structures, π-stacking, halogen-π and CH-π interactions were found. An analysis of the Hirshfeld surface for [{TcOCl₂}₂(μ-O)(μ-pyd)₂], [{TcOCl2}2(μ-O)(μ-trz)₂] and their rhenium analogues showed that the main contribution to the crystalline packing is made by interactions of the type Hal···H/H···Hal (45.4–48.9%), H···H (10.2–15.8%), and O···H/H···O (9.4–16.5%). Full article

Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29 and Jurkat cancer cell lines. All derivatives with a common 3-phenylpropylamino moiety at the 2-position of the triazolopyrimidine scaffold and different halogen-substituted anilines at its 7-position, corresponding to 4′-fluoroaniline (8q), 4′-fluoro-3′-chloroaniline (8r), 4′-chloroaniline (8s) and 4′-bromoaniline (8u), displayed the greatest antiproliferative activity with mean IC_50′s of 83, 101, 91 and 83 nM, respectively. These four compounds inhibited tubulin polymerization about 2-fold more potently than combretastatin A-4 (CA-4), and their activities as inhibitors of [³H]colchicine binding to tubulin were similar to that of CA-4. These data underlined that the 3′,4′,5′-trimethoxyanilino moiety at the 7-position of the [1,2,4]triazolo [1,5-a]pyrimidine system, which characterized compounds 7a–ad, was not essential for maintaining potent antiproliferative and antitubulin activities. Compounds 8q and 8r had high selectivity against cancer cells, and their interaction with tubulin led to the accumulation of HeLa cells in the G2/M phase of the cell cycle and to apoptotic cell death through the mitochondrial pathway. Finally, compound 8q significantly inhibited HeLa cell growth in zebrafish embryos. Full article