Search Results (30)

A series of new quinazolin-2,4-dione derivatives incorporating amide/eight-membered nitrogen-heterocycles 2a–c, in addition, acylthiourea/amide/dithiolan-4-one and/or phenylthiazolidin-4-one 3a–d and 4a–d. The starting compound 1 was prepared by reaction of 4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-benzoyl chloride with ammonium thiocyanate and cyanoacetic acid hydrazide. The reaction of 1 with strong electrophiles, namely, o-aminophenol, o-amino thiophenol, and/or o-phenylene diamine, resulted in corresponding quinazolin-2,4-dione derivatives incorporating eight-membered nitrogen-heterocycles 2a–d. Compounds 3a–d and 4a–d were synthesized in good-to-excellent yield through a one-pot multi-component reaction (MCR) of 1 with carbon disulfide and/or phenyl isocyanate under mild alkaline conditions, followed by ethyl chloroacetate, ethyl iodide, methyl iodide, and/or concentrated HCl, respectively. The obtained products were physicochemically characterized by melting points, elemental analysis, and spectroscopic techniques, such as FT-IR, ¹H-NMR, ¹³C-NMR, and MS. The antibacterial efficacy of the obtained eleven molecules was examined in vitro against two Gram-positive bacterial strains (Staphylococcus aureus and Staphylococcus haemolyticus). Furthermore, Computer-Aided Drug Design (CADD) was performed on the synthesized derivatives, standard drug (Methotrexate), and reported antibacterial drug with the target enzymes of bacterial strains (S. aureus and S. haemolyticus) to explain their binding mode of actions. Notably, our findings highlight compounds 2b and 2c as showing both the best antibacterial activity and docking scores against the targets. Finally, according to ADMET predictions, compounds 2b and 2c possessed acceptable pharmacokinetics properties and drug-likeness properties. Full article

In this study, a new series of cis and trans 5-substituted-3-(dibenzyloxyphosphoryl)isoxazolidines 16a–g were synthesized by the 1,3-dipolar cycloaddition reaction of N-benzyl-C-(dibenzyloxyphosphoryl)nitrone and selected N¹-allyl-N³-benzylquinazoline-2,4-diones. All the obtained trans-isoxazolidines 16a–g and the samples enriched in respective cis-isomers were evaluated for anticancer activity against three tumor cell lines. All the tested compounds exhibited high activity against the prostate cancer cell line (PC-3). Isoxazolidines trans-16a and trans-16b and diastereoisomeric mixtures of isoxazolidines enriched in cis-isomer using HPLC, namely cis-16a/trans-16a (97:3) and cis-16b/trans-16b (90:10), showed the highest antiproliferative properties towards the PC-3 cell line (IC₅₀ = 9.84 ± 3.69–12.67 ± 3.45 μM). For the most active compounds, induction apoptosis tests and an evaluation of toxicity were conducted. Isoxazolidine trans-16b showed the highest induction of apoptosis. Moreover, the most active compounds turned out safe in vitro as none affected the cell viability in the HEK293, HepG2, and HSF cellular models at all the tested concentrations. The results indicated isoxazolidine trans-16b as a promising new lead structure in the search for effective anticancer drugs. Full article

The syntheses of novel 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazolines 12 and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinolines 13 are reported here in six steps starting from various halogeno-quinazoline-2,4-(1H,3H)-diones or substituted anilines. The antiproliferative activities of the products were determined in vitro against a panel of breast (MCF-7 and MDA-MB-231), human adherent cervical (HeLa and SiHa), and ovarian (A2780) cell lines. Disubstituted 6- and 7-phenyl-bis(3-dimethylaminopropyl)aminomethylphenyl-quinazolines 12b, 12f, and 12i displayed the most interesting antiproliferative activities against six human cancer cell lines. In the series of quinoline derivatives, 6-phenyl-bis(3-dimethylaminopropyl)aminomethylphenylquinoline 13a proved to be the most active. G-quadruplexes (G4) stacked non-canonical nucleic acid structures found in specific G-rich DNA, or RNA sequences in the human genome are considered as potential targets for the development of anticancer agents. Then, as small aza-organic heterocyclic derivatives are well known to target and stabilize G4 structures, their ability to bind G4 structures have been determined through FRET melting, circular dichroism, and native mass spectrometry assays. Finally, telomerase inhibition ability has been also assessed using the MCF-7 cell line. Full article

The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including cell proliferation and differentiation, cell survival, and inflammation. Because of emerging data suggesting that JNK3 may play an important role in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease, as well as cancer pathogenesis, we sought to identify JNK inhibitors with increased selectivity for JNK3. A panel of 26 novel tryptanthrin-6-oxime analogs was synthesized and evaluated for JNK1-3 binding (K_d) and inhibition of cellular inflammatory responses. Compounds 4d (8-methoxyindolo[2,1-b]quinazolin-6,12-dione oxime) and 4e (8-phenylindolo[2,1-b]quinazolin-6,12-dione oxime) had high selectivity for JNK3 versus JNK1 and JNK2 and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue cells and interleukin-6 (IL-6) production by MonoMac-6 monocytic cells in the low micromolar range. Likewise, compounds 4d, 4e, and pan-JNK inhibitor 4h (9-methylindolo[2,1-b]quinazolin-6,12-dione oxime) decreased LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of these compounds in the JNK3 catalytic site that were in agreement with the experimental data on JNK3 binding. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems with selectivity for JNK3. Full article

Drug resistance is rising to alarming levels, constituting one of the major threats to global health. The overexpression of efflux pumps and the formation of biofilms constitute two of the most common resistance mechanisms, favoring the virulence of bacteria. Therefore, the research and development of effective antimicrobial agents that can also counteract resistance mechanisms are extremely important. Pyrazino[2,1-b]quinazoline-3,6-diones, from marine and terrestrial organisms and simpler synthetic analogues, were recently disclosed by us as having relevant antimicrobial properties. In this study, using a multi-step approach, it was possible to synthesize new pyrazino[2,1-b]quinazoline-3,6-diones focusing on compounds with fluorine substituents since, to the best of our knowledge, the synthesis of fluorinated fumiquinazoline derivatives had not been attempted before. The new synthesized derivatives were screened for antibacterial activity and, along with previously synthetized pyrazino[2,1-b]quinazoline-3,6-diones, were characterized for their antibiofilm and efflux-pump-inhibiting effects against representative bacterial species and relevant resistant clinical strains. Several compounds showed relevant antibacterial activity against the tested Gram-positive bacterial species with MIC values in the range of 12.5–77 μM. Furthermore, some derivatives showed promising results as antibiofilm agents in a crystal violet assay. The results of the ethidium bromide accumulation assay suggested that some compounds could potentially inhibit bacterial efflux pumps. Full article

A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of N-aryl-N′-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities. Full article

Carbon capture and storage (CCS) and carbon capture and utilization (CCU) are two kinds of strategies to reduce the CO₂ concentration in the atmosphere, which is emitted from the burning of fossil fuels and leads to the greenhouse effect. With the unique properties of ionic liquids (ILs), such as low vapor pressures, tunable structures, high solubilities, and high thermal and chemical stabilities, they could be used as solvents and catalysts for CO₂ capture and conversion into value-added chemicals. In this critical review, we mainly focus our attention on the tuning IL-based catalysts for CO₂ conversion into quinazoline-2,4(1H,3H)-diones from o-aminobenzonitriles during this decade (2012~2022). Due to the importance of basicity and nucleophilicity of catalysts, kinds of ILs with basic anions such as [OH], carboxylates, aprotic heterocyclic anions, etc., for conversion CO₂ and o-aminobenzonitriles into quinazoline-2,4(1H,3H)-diones via different catalytic mechanisms, including amino preferential activation, CO₂ preferential activation, and simultaneous amino and CO₂ activation, are investigated systematically. Finally, future directions and prospects for CO₂ conversion by IL-based catalysts are outlined. This review is benefit for academic researchers to obtain an overall understanding of the synthesis of quinazoline-2,4(1H,3H)-diones from CO₂ and o-aminobenzonitriles by IL-based catalysts. This work will also open a door to develop novel IL-based catalysts for the conversion of other acid gases such as SO₂ and H₂S. 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

Quinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1H,3H)-diones and quinazoline-4(3H)-one guanidine derivatives. In the present work, novel $N^1$,$N^3$-bis-substituted quinazoline-2,4(1H,3H)-dione derivatives bearing two guanidine moieties were synthesized and pharmacologically profiled. The most potent NHE-1 inhibitor 3a also possesses antiplatelet and intraocular-pressure-reducing activity. Compound 4a inhibits NO synthesis and IL-6 secretion in murine macrophages without immunotoxicity and alleviates neutrophil infiltration, edema, and tissue lesions in a model of LPS-induced acute lung injury. Hence, we considered quinazoline derivative 4a as a potential agent for suppression of cytokine-mediated inflammatory response and acute lung injury. Full article

Dipolar cycloaddition of the N-substituted C-(diethoxyphosphonyl)nitrones with N³-allyl-N¹-benzylquinazoline-2,4-diones produced mixtures of diastereoisomeric 3-(diethoxyphosphonyl)isoxazolidines with a N¹-benzylquinazoline-2,4-dione unit at C5. The obtained compounds were assessed for antiviral and antibacterial activities. Several compounds showed moderate inhibitory activities against VZV with EC₅₀ values in the range of 12.63–58.48 µM. A mixture of isoxazolidines cis-20c/trans-20c (6:94) was found to be the most active against B. cereus PCM 1948, showing an MIC value 0.625 mg/mL, and also was not mutagenic up to this concentration. Full article

Indolo[2,1-b]quinazolin-6,12-dione (tryptanthrin) derivatives present important types of nitrogen-containing heterocyclic compounds which are useful intermediate products in organic synthesis and have potential pharmaceutical applications. The new ethyl 5-oxo-5-(((12-oxoindolo[2,1-b]quinazolin-6(12H)-ylidene)amino)oxy)pentanoate (Compound 2) was synthesized. Compound 2 is the first example of a tryptanthrin derivative containing a dicarboxylic acid residue in the side chain. The Z,E-isomerism of Compound 2 was investigated by DFT calculations. Bioavailability was evaluated in silico using ADME predictions. According to the ADME results, Compound 2 is potentially highly bioavailable and has the prospective to be used as the main component for the development of anti-inflammatory drugs. Full article

A series of 5′-phosphorylated (dialkyl phosphates, diaryl phosphates, phosphoramidates, H-phosphonates, phosphates) 1,2,3-triazolyl nucleoside analogues in which the 1,2,3-triazole-4-yl-β-D-ribofuranose fragment is attached via a methylene group or a butylene chain to the N-1 atom of the heterocycle moiety (uracil or quinazoline-2,4-dione) was synthesized. All compounds were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1). Antiviral assays revealed three compounds, 13b, 14b, and 17a, which showed moderate activity against influenza virus A (H1N1) with IC₅₀ values of 17.9 μM, 51 μM, and 25 μM, respectively. In the first two compounds, the quinazoline-2,4-dione moiety is attached via a methylene or a butylene linker, respectively, to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5′-diphenyl phosphate substituent. In compound 17a, the uracil moiety is attached via the methylene unit to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5′-(phenyl methoxy-L-alaninyl)phosphate substituent. The remaining compounds appeared to be inactive against influenza virus A/PR/8/34/(H1N1). The results of molecular docking simulations indirectly confirmed the literature data that the inhibition of viral replication is carried out not by nucleoside analogues themselves, but by their 5′-triphosphate derivatives. Full article

N-heterocyclic compounds, such as quinazolinone derivatives, have significant biological activities. Nowadays, as the demand for environmentally benign, sustainable processes increases, the application of compounds from renewable sources, easily separable heterogeneous catalysts and efficient, alternative activation methods is of great importance. In this study, we have developed a convenient, green procedure for the preparation of 3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione through a double cyclocondensation cascade using anthranilamide and ethyl levulinate. Screening of various heterogeneous Brønsted acid catalysts showed that Amberlyst^® 15 is a convenient choice. By applying mechanochemical activation in the preparation of this N-heterotricyclic compound for the first time, it was possible to shorten the necessary time to three hours compared to the 24 h needed under conventional conditions to obtain a high yield of the target product. Full article

In this paper, we report on the design and synthesis of a novel series of quinazoline-2,4(1H,3H)-dione derivatives as fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV to identify and develop antimicrobial agents to prevent bacterial resistance problems. Their structures were confirmed using spectroscopic analyses (IR, NMR, and EI-MS). The novel quinazoline-2,4(1H,3H)-dione derivatives were evaluated for their antimicrobial activities against Gram-positive and Gram-negative bacterial strains using the Agar well diffusion method to study the antimicrobial activities and compared them with the standard drugs. Most compounds displayed moderate activity. Among the tested compounds, the most promising compounds 13 and 15 provided broad bioactive spectrum against Gram-positive and Gram-negative strains compared to the standard drugs. Full article

New tetrahydropyrazino[2,3-c]quinolin-5(6H)-ones were prepared from 3-chloroquinoline-2,4(1H,3H)-diones and ethylene diamine. In their reaction with HNCO, an unprecedented molecular rearrangement produced new types of hydantoin derivatives. All prepared compounds were characterized on the basis of their ¹H, ¹³C, and ¹⁵N NMR and ESI mass spectra and some were authenticated by X-ray analysis of single crystalline material. A proposed mechanism for rearrangement is discussed in this essay. The CDK and ABL inhibition activity as well as in vitro cytotoxicity of the prepared compounds was also tested. Full article