Search Results (28)

False cleavers (Galium spurium L.) is a broadleaf weed species that affects wheat productivity because of its strong competition for resources. It has developed resistance to acetolactate synthase (ALS) inhibitors, such as sulfonylureas and triazolopyrimidines, which are herbicides widely used in durum wheat. Integrated weed management programs can contribute to the control of this species and delay the evolution of herbicide resistance. Thus, a two-year field experiment was conducted to evaluate the effects of sowing time, variety, and herbicides on crop yield, density, and dry weight of a false cleavers population with resistance to ALS inhibitors. In both growing seasons, a split-split-plot design was used with three replicates. The sowing date was chosen as the main plot factor, durum wheat varieties as the subplot factor, and herbicides as the sub-subplot factor. The herbicide treatments were: (1) metsulfuron-methyl/bensulfuron-methyl (4/50 g a.i. ha⁻¹), (2) aminopyralid/florasulam (9.9/4.95 g a.i. ha⁻¹), (3) pyroxsulam and florasulam/2,4-D (18.75 + 4.725/225 g a.i. ha⁻¹), (4) 2,4-D/bromoxynil (633.15/601.2 g a.i. ha⁻¹), non-treated control, and hand-weeded control for the first season, while in the second season one more herbicide treatment (halauxifen-methyl/florasulam, 5.6/5.15 g a.i. ha⁻¹) was added. Herbicide application was performed on 10 March 2021 and 28 March 2022, when the crop was at the end of tillering and the beginning of stem elongation. The results showed that the density of false cleavers was not affected by the variety or sowing time. However, its dry weight was 17.3–23.4% higher in early sowing (16 November in 2020 and 8 November 2021) than in late sowing (24 December 2020 and 2 December 2021). Among the herbicides tested, 2,4-D/bromoxynil and halauxifen-methyl/florasulam effectively controlled false cleavers, showing greater efficacy in late sowing (>88%), which ultimately led to a higher yield. In conclusion, our two-year findings demonstrate that delayed sowing as part of an integrated weed management strategy can contribute to controlling resistant populations of false cleavers to ALS-inhibiting herbicides without affecting the quantity and quality of durum wheat yield in areas with a Mediterranean climate. Full article

Triazolopyrimidine and its analogs represent an important scaffold in medicinal chemistry research. The heterocycle of 1,2,4-triazolo[1,5-a] pyrimidine (1,2,4-TAP) serves as a bioisostere candidate for purine scaffolds, N-acetylated lysine, and carboxylic acid. This study modeled the quantitative structure–activity relationship (QSAR) of 125 congeners of 1,2,4-TAP from the ChEMBL database in the inhibition of Plasmodium falciparum using six machine learning algorithms. The most significant features among 306 molecular descriptors, including one molecular outlier, were selected using recursive feature elimination. A ratio of 20% was used to split the x- and y-matrices into 99 training and 24 test compounds. The regression models were built using machine learning sci-kit-learn algorithms (multiple linear regression (MLR), k-nearest neighbours (kNN), support vector regressor (SVR), random forest regressor (RFR) RIDGE regression, and LASSO). Model performance was evaluated using the coefficient of determination (R²), mean squared error (MSE), mean absolute error (MAE), root mean squared error (RMSE), p-values, F-statistic, and variance inflation factor (VIF). Five significant variables were considered in constructing the model (p < 0.05) with the following regression equation: pIC₅₀ = 5.90 − 0.71npr1 − 1.52pmi3 + 0.88slogP − 0.57vsurf-CW2 + 1.11vsurf-W2. On five-fold cross-validation, three algorithms—kNN (MSE = 0.46, R² = 0.54, MAE = 0.54, RMSE = 0.68), SVR (MSE = 0.33, R² = 0.67, MAE = 0.46, RMSE = 0.57), and RFR (MSE = 0.43, R² = 0.58, MAE = 0.51, RMSE = 0.66)—showed strong robustness, efficiency, and reliability in predicting the pIC₅₀ of 1,2,4-triazolo[1,5-a]pyrimidine. The models provided useful data on the functionalities necessary for developing more potent 1,2,4-TAP analogs as anti-malarial agents. Full article

Background: Recently, pyrido[2,3-d] pyrimidine, triazolopyrimidine, thiazolopyrimidine, quinoline, and pyrazole derivatives have gained attention due to their diverse biological activities, including antimicrobial, antioxidant, antitubercular, antitumor, anti-inflammatory, and antiviral effects. Objective: The synthesis of new heterocyclic compounds including 5-quinoline-pyrido[2,3-d] pyrimidinone (1–2, 4, 6–7), 6-quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidinone (3, 5, 8–10), 1,2,4-triazole-6-quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidinone (11–13), and pyrido[2,3-d]thiazolo[3,2-a]pyrimidine-ethyl-(pyridine)-9-thiaazabenzo[cd]azulenone (14) derivatives was performed with high yields while evaluating antimicrobial activities. Methods: A new series of quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidine derivatives were prepared using a modern style and advanced technology, resulting in high yields of these new compounds. Various reagents were utilized, specifically tailored to the production needs of each compound, through reactions that included alkylation, addition, condensation, acylation, the formation of Schiff bases, and intramolecular cyclization. Results: The chemical structures of the new compounds were determined using spectroscopy analyses, including IR, NMR, and MS, achieving good yields ranging from 68% to 90% under mild conditions in a regular system. All compounds were tested for in vitro antimicrobial activity and compared to standard drugs, specifically cefotaxime sodium and nystatin. The results showed that compounds 10 to 14 exhibited excellent antimicrobial activity, with a minimum inhibitory concentration (MIC) of 1 to 5 µmol/mL, compared to that of the standard drugs, which had MIC values of 1 to 3 µmol/mL. Furthermore, molecular docking studies were conducted to explore the interactions of specific compounds with antimicrobial target proteins. The findings revealed that compounds 10 to 14 displayed significant binding energies, with ΔG values ranging from −7.20 to −11.70 kcal/mol, indicating effective binding to the active sites of antimicrobial protein receptors. Conclusions: The SAR study confirmed a relationship between antimicrobial activity and the tested compounds. Molecular docking demonstrated that compounds 10, 11, 12, 13, and 14 exhibited significant binding energy, effectively interacting with the active sites of antimicrobial protein receptors. This consistent finding supports that these new compounds’ practical and theoretical studies align regarding their antimicrobial activity. Full article

Inhibition of the Embryonic Ectoderm Development (EED) subunit in Polycomb Repressive Complex 2 (PRC2) can inhibit tumor growth. In this paper, we selected six experimentally designed EED competitive Inhibitors of the triazolopyrimidine derivatives class. We investigated the difference in the binding mode of the natural substrate to the Inhibitors and the effects of differences in the parent nuclei, heads, and tails of the Inhibitors on the inhibitory capacity. The results showed that the binding free energy of this class of Inhibitors was close to or lower compared to the natural substrate, providing an energetic basis for competitive inhibition. For the Inhibitors, the presence of a strong negatively charged group at the 6-position of the parent nucleus or the 8′-position of the head would make the hydrogen atom on the head imino group prone to flip, resulting in the vertical movement of the parent nucleus, which significantly decreased the inhibitory ability. When the 6-position of the parent nucleus was a nonpolar group, the parent nucleus would move horizontally, slightly decreasing the inhibitory ability. When the 8′-position of the head was methylene, it formed an intramolecular hydrophobic interaction with the benzene ring on the tail, resulting in a significant increase in inhibition ability. Full article

A series of new [1,2,4]triazolo[4,3-a]pyrimidine derivatives was prepared using a one-pot three-component synthesis from 5-amino-1-phenyl-1H-1,2,4-triazoles, aromatic aldehydes and ethyl acetoacetate. The compound structures were confirmed by IR, ¹H-NMR, ¹³C-NMR, HRMS and X-ray analyses. The biological activity of these compounds as antitumor agents was evaluated. Their antitumor activities against cancer cell lines (MDA-MB-231 and MCF-7) were tested by the MTT in vitro method. Among them, compounds 4c and 4j displayed the best antitumor activity with IC₅₀ values of 17.83 μM and 19.73 μM against MDA-MB-231 and MCF-7 cell lines, respectively, compared to the Cisplatin reference. Full article

False cleavers (Galium spurium L.) is an annual broadleaf weed, commonly found in cereal crops around the world. It reduces crop yields mainly by the competition for nutrients and plant lodging, which decreases the photosynthetic rate of cultivated plants. Two field experiments were carried out in different locations to examine the efficacy of post-emergence herbicides against false cleavers in durum wheat (Triticum durum Desf.). Herbicides that belong to sulfonylureas, triazolopyrimidines, and other groups (e.g., nitriles and synthetic auxins) were applied. The results revealed that the herbicide florasulam + aminopyralid provided low efficacy (57%) against this weed species, while the most effective herbicides were bromoxynil + 2,4-D and halauxifen-methyl + florasulam. Bromoxynil + 2,4-D efficacy against false cleavers was 73% and 97% at Domokos and Velestino, respectively, while halauxifen-methyl + florasulam efficacy ranged between 89% and 97%. Moreover, the herbicides metsulfuron-methyl + bensulfuron-methyl and pyroxsulam/florasulam + 2,4-D provided low efficacy (<11%) against false cleavers, revealing resistance to ALS-inhibiting herbicides. Regarding the impact of false cleavers and other weed species on the growth of durum wheat, the results showed that the greatest dry biomass (8508.3–8922.7 kg ha⁻¹ and 13,041.4–13,523 kg ha⁻¹ at Domokos and Velestino, respectively) was found in the bromoxynil + 2,4-D, halauxifen-methyl + florasulam, and weed-free treatments. Similar results were also recorded for 1000-seed weights and crop yields, while there were no statistically significant differences among the treatments for spike length. Finally, our results revealed that the herbicides bromoxynil + 2,4-D and halauxifen-methyl + florasulam effectively controlled the resistant false cleavers population. However, it is important to note that halauxifen-methyl + florasulam was recently registered in Greece and other countries and, thus, should be used sensibly by farmers in a rotation with other herbicides to prevent the development of resistant populations. Full article

In this work, we describe the design, synthesis, and structure-activity relationship of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-a]pyrimidines as inhibitors of Casein kinase 2 (CK2). At first, we optimized the reaction conditions for the azide-nitrile cycloaddition in the series of 6-cyano-7-aminoazolopyridimines and sodium azide. The regioselectivity of this process has been shown, as the cyano group of the pyrimidine cycle was converted to tetrazole while the nitrile of the azole fragment did not react. The desired tetrazolyl-azolopyrimidines were obtained in a moderate to excellent yields (42–95%) and converted further to water soluble sodium salts by the action of sodium bicarbonate. The obtained 6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidines 2a–k and their sodium salts 3a–c, 3g–k showed nano to low micromolar range of CK2 inhibition while corresponding [1,2,4]triazolopyrimidines 10a–k were less active (IC₅₀ > 10 µM). The leader compound 3-phenyl-6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidine 2i as CK2 inhibitor showed IC₅₀ 45 nM. Full article

This study aims to synthesize a new series of furochromone derivatives, evaluate their antimicrobial properties, and improve the permeability of potent compounds to inhibit different types of bacteria and fungi. Hence, Substituted furo[3,2-g]chromene-6-carbonitrile (3a,b) readily form 7-amino-5-methyl-furo [3,2-g]chromene-6-carbonitrile (4a,b) via reduction using sodium borohydride in methanol. The same compounds of (4a,b) were used as starting materials for the synthesis of new furochromone derivatives such as furochromeno [2,3-d]pyrimidines, N- (6-cyano- 5-methyl-furochromene) acetamide, N-(6-cyano-5-methyl-furo chromene)-2-phenyl acetamide, N- (6-cyano-5-methyl-furochromene) formimidate, furochromeno[1,2,4]triazepin-5-amine, furochrom ene-6-carboxamide, furochromeno[1,2,4]triazolopyrimidines, and furochromeno[2,3-b]quinolin- 6-amine. The structures of the new compounds were determined using spectroscopy: Nuclear Magnetic Resonance (¹H, ¹³C), Mass spectra, Infrared, and elemental analysis. Molecular docking studies were conducted to investigate the binding patterns of the prepared compounds against DNA-gyrase (PDB 1HNJ). The results displayed that compounds furochromenotriazolopyrimidine (20a,b), furochromenoquinolin-6-amine (21a,b), furochromenotriazepin-amine (9a,b), and furo- chromenopyrimidine-amine (19a,b) were excellent antimicrobials. Full article

A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC₅₀ values of 30–43, 160–240 and 67–160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC₅₀: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies. 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

Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds 2, 3a, 3b, 4, 11 and 13 showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds 2 and 11 were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, 2 and 11 displayed drug-like in silico ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds 2, 3a, 3b, 4, 11 and 13. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers. Full article

The platinum(II) complexes of general formula [PtCl₂(dstp)(S-donor)] were dstp 5,7-dimethyl-1,2,4-triazolo[1,5-a]-pyrimidine (dmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp), 5-methyl-7-isobutyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) or 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp), whereas S-tetrahydrothio-phene-1-oxide (TMSO) or diphenyl sulfoxide (DPSO) were synthesized in a one-pot reaction. Here, we present experimental data (¹H, ¹³C, ¹⁵N, ¹⁹⁵Pt NMR, IR, X-ray) combined with density functional theory (DFT) computations to support and characterize structure–spectra relationships and determine the geometry of dichloride platinum(II) complexes with selected triazolopyrimidines and sulfoxides. Based on the experimental and theoretical data, factors affecting the stability of platinum(II) complexes have been determined. Full article

Cases of weed resistant to herbicides have changed the dynamics of agricultural areas in Brazil, and in recent years, Erigeron species have caused major problems to farmers in the country, mainly in relation to the ineffectiveness of herbicide treatments used. The objective of this study was to confirm the cross-resistance to ALS inhibitors in populations of Erigeron sumatrensis as well as to investigate the existence of mutations in the site of action of ALS-inhibiting herbicides. To do this, 30 populations collected in the 2016/2017 crop season were grown in a greenhouse. Dose–response (chlorimuron-ethyl and cloransulam-methyl), inhibition of cytochrome P-450 with malathion, and ALS gene sequencing experiments were carried out in the F1 generations of two fleabane populations. The results proved the cross-resistance to chlorimuron-ethyl and cloransulam-methyl herbicides applied in the post-emergence of the resistant population of E. sumatrensis. The higher activity of P450 enzymes is unlikely responsible for the resistance of the population studied. The resistance mechanism found in R was the target site mutation Pro197Ser at the ALS gene. This is the first study in Brazil to identify a target-site change as a survival mechanism in E. sumatrensis for the resistance to ALS-inhibiting herbicides. Full article

The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2. Full article

In an attempt to increase the biological activity of the 1,2,4-triazolo[1,5-a]pyrimidine scaffold through complexation with essential metal ions, the complexes trans-[Cu(mptp)₂Cl₂] (1), [Zn(mptp)Cl₂(DMSO)] (2) (mptp: 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidine), [Cu₂(dmtp)₄Cl₄]·2H₂O (3) and [Zn(dmtp)₂Cl₂] (4) (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine), were synthesized and characterized as new antiproliferative and antimicrobial species. Both complexes (1) and (2) crystallize in the P2₁/n monoclinic space group, with the tetrahedral surroundings generating a square-planar stereochemistry in the Cu(II) complex and a tetrahedral stereochemistry in the Zn(II) species. The mononuclear units are interconnected in a supramolecular network through π–π interactions between the pyrimidine moiety and the phenyl ring in (1) while supramolecular chains resulting from C-H∙∙∙π interactions were observed in (2). All complexes exhibit an antiproliferative effect against B16 tumor cells and improved antibacterial and antifungal activities compared to the free ligands. Complex (3) displays the best antimicrobial activity against all four tested strains, both in the planktonic and biofilm-embedded states, which can be correlated to its stronger DNA-binding and nuclease-activity traits. Full article