Search Results (15)

Natural products are a main source of new chemical entities for use in drug and pesticide discovery. In order to discover lead compounds with high herbicidal activity, a series of new pyrido[2,3-d] pyrimidine derivatives were designed and synthesized using 2-chloronicotinic acid as the starting material. Their structures were characterized with ¹H NMR, ¹³C NMR and HRMS, and the herbicidal activities against dicotyledonous lettuce (Lactuca sativa), field mustard (Brassica campestris), monocotyledonous bentgrass (Agrostis stolonifera) and wheat (Triticum aestivum) were determined. The results indicated that most of the pyrido[2,3-d] pyrimidine derivatives had no marked inhibitory effect on lettuce at 1 mM. However, most of the pyrido[2,3-d] pyrimidine derivatives possessed good activity against bentgrass at 1 mM. Among them, the most active compound, 3-methyl-1-(2,3,4-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2o), was as active as the positive controls, the commercial herbicides clomazone and flumioxazin. Molecular simulation was performed with molecular docking and DFT calculations. The docking studies provided strong evidence that 2o acts as an herbicide by inhibition of protoporphyrinogen oxidase. However, the physiological results indicate that it does not act on this target in vivo, implying that it could be metabolically converted to a compound with a different molecular target. Full article

A sulfonated poly-4-vinyl pyridinium (PVPy-IL-B-SO₃H) containing an acidic pyridinium/HSO₃⁻ ionic liquid moiety was prepared and used as a catalyst for the three-component reaction of malononitrile with 1-alkylindoline-2,3-diones and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione or methyl 5-hydroxy-1H-pyrazole-3-carboxylate, leading to methyl 6′-amino-5′-cyano-2-oxo-2′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-3′-carboxylates or -3,4′-pyrano[2,3-d]pyrimidine]-6′-carbonitrile derivatives under ultrasonic irradiation conditions. The solid catalyst allows easy separation, is cheap, produces high yields under mild conditions, and does not require column chromatography for product isolation and purification. Full article

The synthesis of a novel uracil derivative, 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4), is reported via a four-component reaction involving an α-chloroketone (1), an aliphatic isocyanate (2), a primary aromatic amine (3) and carbon monoxide. The proposed reaction mechanism involves a Pd-catalyzed carbonylation of 2-chloro-1-phenylethan-1-one (1), leading to a β-ketoacylpalladium key intermediate, and, at the same time, in situ formation of non-symmetrical urea deriving from cyclohexyl isocyanate (2) and p-toluidine (3). After a chemo-selective acylation of the non-symmetrical urea and the subsequent cyclization of the acylated intermediate, 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4) is formed. Uracil derivative 4 was isolated in good yield (73%) and fully characterized by ¹H, ¹³C, 2D ¹H-¹³C HSQC and 2D ¹H-¹³C HMBC NMR, FT-IR spectroscopy and GC-MS spectrometry. Full article

In this paper, the chitosan-functionalized ionic liquid is modified with superparamagnetic iron oxide nanoparticles to form a novel and reusable catalyst (SPION@CS-IL), which was carried out using an ultrasonic promoted approach. Transmission electron microscopy (TEM), vibrating-sample magnetometer (VSM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), and thermogravimetric analysis (TGA) are some of the techniques that are used to fully characterize SPION@CS-IL. The created nanoparticles were discovered to be a reusable heterogeneous superparamagnetic catalyst for the environmentally friendly one-pot synthesis of pyrido[2,3-d]pyrimidine derivatives using a simple three-component reaction approach involving thiobarbituric acid, 4-hydroxy coumarin, and various aromatic aldehydes. The method is studied by performing the reaction under ultrasonic irradiation, while the approach is a “green” method, it uses water as the solvent. The isolated yields of the synthesized products are very advantageous. The catalyst has outstanding reusability and is easily removed from the products via filtration (5 runs). Short reaction times, low catalyst loadings, the nanocatalyst’s capacity to be recycled five times, and the absence of harmful chemical reagents are all significant benefits of this environmentally benign process. Full article

Novel derivatives based on 6-methyluracil and condensed uracil, 2,4-quinazoline-2,4-dione, were synthesized with terminal meta- and para-benzoate moieties in polymethylene chains at the N atoms of the pyrimidine ring. In the synthesized compounds, the polymethylene chains were varied from having tris- to hexamethylene chains and quaternary ammonium groups; varying substituents (ester, salt, acid) at benzene ring were introduced into the chains and benzoate moieties. In vivo biological experiments demonstrated the potency of these compounds in decreasing the number of β-amyloid plaques and their suitability for the treatment of memory impairment in a transgenic model of Alzheimer’s disease. Full article

A thieno[2,3-d]pyrimidine derivative 3 bearing a 4,5-imidazolidinedione moiety, 1,3-bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)imidazolidine-4,5-dione, was efficiently synthesized in 66% yield by the reaction of N,N′-bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)methanediamine 2 with oxalyl chloride in the presence of pyridine in refluxing dichloroethane for 10 h. The structure of the new synthesized compounds was fully characterized by 1H, 13C NMR, IR spectroscopy, mass-spectrometry and elemental analysis. Full article

The current work aims to design and synthesis a new series of isatin derivatives and greatly enhances their cytotoxic activity. The derivatives 3-((bromophenyl) imino)-1-(morpholino (pyridine) methyl) indolin-2-one, 2-((oxoindoline) amino) benzoic acid, 3-(thiazolo-imino) indolinone, ethyl-2-((oxoindolin-3-ylidene)amino)-benzothiophene-3-carboxylate, 1-(oxoindoline)-benzo[4,5] thieno [2,3-d]pyrimidin-4(1H)-one, ethyl-2-(2-oxoindoline) hydrazine-1-carboxylate, N-(mercapto-oxo-pyrimidine)-2-(oxoindoline) hydrazine-1-carboxamide, N-(oxo-thiazolo[3,2-a] pyrimidine)-2-(oxoindolin-ylidene) hydrazine-carboxamide, 3-((amino-phenyl) amino)-3-hydroxy- indolinone, 3-((amino-phenyl) imino)-indolinone, 2-(2-((oxoindoline) amino) phenyl) isoindolinone, 2-(oxoindoline) hydrazine-carbothioamide, 5′-thioxospiro[indoline-3,3′-[1,2,4]triazolidin]-one, 5′-amino-spiro[indoline-3,2′-[1,3,4]thiadiazol]-2-one and 3-((2-thioxo-imidazo[4,5-b]quinoxaline) imino) indolinone were synthesized from the starting material 1-(morpholino (pyridine) methyl) indoline-2,3-dione and evaluated for their in vitro cytotoxic activity against carcinogenic cells. The new chemical structures were evidenced using spectroscopy (IR, NMR and MS) and elemental analysis. The results show that compounds imidazo[4,5-b]quinoxaline-indolinone, thiazolopyrimidine-oxoindoline, pyrimidine-oxoindoline-hydrazine-carboxamide, spiro[indoline-3,2′-[1,3,4] thiadiazol]-one and spiro[indoline-3,3′-[1,2,4]triazolidin]-one have excellent anti-proliferative activities against different human cancer cell lines such as gastric carcinoma cells (MGC-803), breast adenocarcinoma cells (MCF-7), nasopharyngeal carcinoma cells (CNE2) and oral carcinoma cells (KB). Full article

The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors’ chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione in particular were identified. Full article

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease. Full article

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a–c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV. Full article

4H-3λ²-Thieno[3,2-d]pyrimidin-4-one derivatives are of interest as biologically active compounds. In this communication, 2-(chloromethyl)-4H-3λ²-thieno[3,2-d]pyrimidin-4-one (1) was investigated in the reaction with ammonia, potassium phthalimide, and other basic agents. The dimerization product—8,18-dithia-1,4,11,14-tetrazapentacyclo[11.7.0.0^3,11.0^5,9.0^15,19]icosa-3,5(9),6,13,15(19),16-hexaene-10,20-dione was formed in the reaction with potassium phthalimide in DMF, by heating at 110 °C for 5 h. The structure of the newly synthesized compound was established by means of elemental analysis, high resolution mass-spectrometry, ¹H, ¹³C NMR, and IR spectroscopy, and mass-spectrometry. Full article

Bromination of N-substituted homophthalimides and tetrahydropyrido[4,3-d]- pyrimidine-5,7-diones produces 4,4-dibromohomophthalimide and 8,8-dibromo-tetrahydropyrido[4,3-d]pyrimidine-5,7-dione derivatives, respectively, that can be used as precursors for spiro derivatives. The dibromo derivatives react with different binucleophilic reagents to produce several spiroisoquinoline and spirotetrahydropyrido[4,3-d]- pyrimidine-5,7-dione derivatives, respectively. Reaction of the dibromo derivatives with malononitrile produces dicyanomethylene derivatives which react with different binucleophiles to produce new spiro derivatives. All new compounds are prepared by using the usual chemical conditions and microwave assisted conditions. The latter conditions improved the reaction yields, reduced reaction times and ameliorated the effects on the surrounding environment as the reactions are carried out in closed systems. Structures of the newly synthesized compounds are proved using spectroscopic methods such as IR, MS, ¹H-NMR and ¹³C-NMR and elemental analyses. Some of the newly synthesized compounds were tested for their antimicrobial activities, whereby four of them showed moderate activities and the rest showed low or no activities towards the investigated species. Full article

New 7-thio derivatives of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione have been synthesized by the reaction of 3-cyclohexyl-7-thio-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with alkylhalogenides. The synthesized compounds were tested for antioxidant activity on the model of Fe²⁺-dependent oxidation of adrenaline in vitro. It was found that the antiradical activity of 7-thio derivatives of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione significantly depends on the structure of the substituent which is part of the thioether fragment of the base molecule. Full article

Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH₃-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET). Full article

(9-Methyl-5,6-dihydronaphtho[1',2':4,5]thieno[2,3-d]pyrimidin-11-yl)hydrazine (1) was used as a precursor for preparation of some novel 1-(9-methyl-5,6- dihydronaphtho[1',2':4,5]thieno[2,3-d]pyrimidin-11-yl)-1H-pyrazoles 2–7, -1H-isoindole- 1,3(2H)-dione 8, and -pyridazin-3(2H)-one 9. Moreover, the acyclic C-nucleosides 10 and 11 were prepared by treating compound 1 with D-glucose. The in vitro antimicrobial activity of the tested compounds was evaluated by measuring the zone diameters and some of the prepared products showed potent antimicrobial activity in compared with those of well known drugs (standard). In general, the non-acetylated sugar hydrazone derivative 10 showed the highest antibacterial and antifungal potency among the tested compounds and standard with IZ = 22, 21 and 22 mm and MIC = 62.5 and 31.25 μg/ml, respectively. Full article