Search Results (27)

An important field of research in medicinal and organic chemistry involves halogen-containing heterocyclic synthones, which form the backbone of more complex organic compounds. This study aimed to design and synthesize 28 novel derivatives of 7-aryl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one. The derivatives were created from 7-bromoquinoline intermediates to evaluate their potential as cholinesterase inhibitors for treating neurodegenerative diseases such as Alzheimer’s disease. The conditions for the Suzuki–Miyaura cross-coupling reaction were optimized to improve yield and purity. The derivatives were evaluated for their anticholinesterase activity using Ellman’s method, revealing that it most effectively inhibited cholinesterase within the micromolar range. 7-(3-Chloro-4-fluorophenyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one derivative exhibited the highest inhibitory potency, with an IC₅₀ value of 6.084 ± 0.26 μM. Additionally, molecular dynamics simulations provided insight into how this lead compound interacts with the enzyme, suggesting its potential as a drug candidate for Alzheimer’s disease. Full article

The significant synthetic potential and reactivity of tetracyanoethylene (TCNE) have captured the interest of numerous chemical communities. One of the most promising, readily achievable, yet least explored pathways for the reactivity of TCNE involves its interaction with arylamines. Typically, the reaction proceeds via tricyanovinylation (TCV); however, deviations from the standard chemical process have been observed in some instances. These include the formation of heterocyclic structures through tricyanovinyl intermediates, aliphatic dicarbonitriles through the cleavage of the C–C bond of a tetracyanoethyl substituent, complexation, and various pericyclic reactions. Therefore, the objective of this study is to review the diverse modes of interaction of TCNE with aromatic nitrogen-containing compounds and to focus the attention of the chemical community on the synthetic capabilities of this reagent, as well as the various biological and optical activities of the structures synthesized based on TCNE. Full article

Two series of novel [1,2,4]triazolo[4,3-c]- and [1,2,4]triazolo[1,5-c]quinazoline fluorophores with 4′-amino[1,1′]-biphenyl residue at position 5 have been prepared via Pd-catalyzed cross-coupling Suzuki–Miyaura reactions. The treatment of 2-(4-bromophenyl)-4-hydrazinoquinazoline with orthoesters in solvent-free conditions or in absolute ethanol leads to the formation of [4,3-c]-annulated triazoloquinazolines, whereas [1,5-c] isomers are formed in acidic media as a result of Dimroth rearrangement. A 1D-NMR and 2D-NMR spectroscopy, as well as a single-crystal X-ray diffraction analysis, unambiguously confirmed the annelation type and determined the molecular structure of p-bromophenyl intermediates and target products. Photophysical properties of the target compounds were investigated in two solvents and in the solid state and compared with those of related 3-aryl-substituted [1,2,4]triazolo[4,3-c]quinazolines. The exclusion of the aryl fragment from the triazole ring has been revealed to improve fluorescence quantum yield in solution. Most of the synthesized structures show moderate to high quantum yields in solution. Additionally, the effect of solvent polarity on the absorption and emission spectra of fluorophores has been studied, and considerable fluorosolvatochromism has been stated. Moreover, electrochemical investigation and DFT calculations have been performed; their results are consistent with the experimental observation. Full article

Oxidative stress, COX-2, LDHA and hyperglycemia are interlinked contributing pathways in the etiology, progression and metastasis of colon cancer. Additionally, dysregulated apoptosis in cells with genetic alternations leads to their progression in malignant transformation. Therefore, quinazolinones 3a–3h and 5a–5h were synthesized and evaluated as antioxidants, enzymes inhibitors and cytotoxic agents against LoVo and HCT-116 cells. Moreover, the most active cytotoxic derivatives were evaluated as apoptosis inducers. The results indicated that 3a, 3g and 5a were efficiently scavenged DPPH radicals with lowered IC₅₀ values (mM) ranging from 0.165 ± 0.0057 to 0.191 ± 0.0099, as compared to 0.245 ± 0.0257 by BHT. Derivatives 3h, 5a and 5h were recognized as more potent dual inhibitors than quercetin against α-amylase and α-glucosidase, in addition to 3a, 3c, 3f and 5b–5f against α-amylase. Although none of the compounds demonstrated a higher efficiency than the reference inhibitors against COX-2 and LDHA, 3a and 3g were identified as the most active derivatives. Molecular docking studies were used to elucidate the binding affinities and binding interactions between the inhibitors and their target proteins. Compounds 3a and 3f showed cytotoxic activities, with IC₅₀ values (µM) of 294.32 ± 8.41 and 383.5 ± 8.99 (LoVo), as well as 298.05 ± 13.26 and 323.59 ± 3.00 (HCT-116). The cytotoxicity mechanism of 3a and 3f could be attributed to the modulation of apoptosis regulators (Bax and Bcl-2), the activation of intrinsic and extrinsic apoptosis pathways via the upregulation of initiator caspases-8 and -9 as well as executioner caspase-3, and the arrest of LoVo and HCT-116 cell cycles in the G2/M and G1 phases, respectively. Lastly, the physicochemical, medicinal chemistry and ADMET properties of all compounds were predicted. 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

Amino-[1,1′]-biphenyl-containing 3-aryl-[1,2,4]triazolo[4,3-c]quinazoline derivatives with fluorescent properties have been designed and synthesized. The type of annelation of the triazole ring to the pyrimidine one has been unambiguously confirmed by means of an X-ray diffraction (XRD) method; the molecules are non-planar, and the aryl substituents form the pincer-like conformation. The UV/Vis and photoluminescent properties of target compounds were investigated in two solvents of different polarities and in a solid state. The samples emit a broad range of wavelengths and display fluorescent quantum yields of up to 94% in toluene solutions. 5-(4’-Diphenylamino-[1,1′]-biphenyl-4-yl)-3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-c]quinazoline exhibits the strongest emission in toluene and a solid state. Additionally, the solvatochromic properties were studied for the substituted [1,2,4]triazolo[4,3-c]quinazolines. Moreover, the changes in absorption and emission spectra have been demonstrated upon the addition of water to MeCN solutions, which confirms aggregate formation, and some samples were found to exhibit aggregation-induced emission enhancement. Further, the ability of triazoloquinazolines to detect trifluoroacetic acid has been analyzed; the presence of TFA induces changes in both absorption and emission spectra, and acidochromic behavvior was observed for some triazoloquinazoline compounds. Finally, electronic-structure calculations with the use of quantum-chemistry methods were performed for synthesized compounds. Full article

Design and synthesis of 2-(aryl/thiophen-2-yl)quinazolin-4(3H)-ones and 4-cyano-2-arylquinazolines with Et₂N-, Ph₂N- or carbazol-9-yl- electron donating fragment are described. The key photophysical properties of these compounds have been studied by UV/Vis absorption and fluorescence spectroscopy in solvents of different polarity (toluene and MeCN). 2-(Aryl/thiophen-2-yl)quinazolin-4(3H)-ones show fluorescence in blue-green region in toluene solution with quantum yields up to 89% in the case of 2-(4’-N,N-diphenylamino[1,1’-biphenyl]-4-yl)-quinazolin-4(3H)-one. Moreover, triphenylamino derivative based on quinazolin-4(3H)-one with para-phenylene linker displays the highest quantum yield of 40% in powder. The fluorescence QY of Et₂N and Ph₂N derivatives decrease when going from toluene to MeCN solution, whereas carbazol-9-yl counterparts demonstrate strengthening of intensity that emphasizes the strong influence of donor fragment nature on photophysical properties. 4-Cyanoquinazolines are less emissive in both solvents, as well as, in solid state. The introduction of cyano group into position 4 leads to orange/red colored powder and dual emission bands. Some molecules demonstrate the increase in emission intensity upon addition of water to MeCN solution. According to frontier molecular orbitals (HOMO, LUMO) calculations, the energy gap of 4-cyanoquinazoline decreases by more than 1 eV compared to quinazolin-4-one, that is consistent with experimental data. Full article

A simple and highly efficient protocol for the synthesis of derivatives 7, 7-dimethyl-4-phenyl-2-thioxo-2, 3, 4, 6, 7, 8-hexahydro-1H-quinazoline-5-one from 5, 5-dimethyl cyclohexane-1, 3-dione (4a–4h) (dimedone) has been described. The aryl aldehydes were substituted with thiourea in the presence of synthesized zinc ferrite nanocatalyst, which increased the yield under reflux through condensation, followed by cyclization to give desired products. The other advantages are that it is eco-friendly and economically affordable for large-scale production. Structural validation and characterization of all the newly synthesized compounds were evaluated by spectral analysis (mass spectrometry, proton nuclear magnetic resonance (¹HNMR), and Carbon-13 nuclear magnetic resonance(¹³CNMR)spectroscopies. The structure of antibacterial and antifungal assays was performed with the newly synthesized compounds. The antimicrobial activity of title compounds possessing electron-withdrawing groups such as (4e–4h) (Cl, Br, and cyano group) exhibited more active potential than the electron-donating groups, C₆H₅,4-C₆H₄, 3-OC₂H₅-4OH-C₆H₃, etc., (4a–4d) containing moiety. Full article

Copper-catalyzed Csp2–Csp2 bond forming reactions through C–H activation are still one of the most useful strategies for the diversification of heterocyclic moieties using various coupling partners. A catalytic protocol for the C–H (hetero)arylation of thiazolo[5,4-f]quinazolin-9(8H)-ones and more generally fused-pyrimidinones using catalyst loading of CuI with diaryliodonium triflates as aryl source under microwave irradiation has been disclosed. The selectivity of the transfer of the aryl group was also disclosed in the case of unsymmetrical diaryliodonium salts. Specific phenylation of valuable fused-pyrimidinones including quinazolinone are provided. This strategy enables a rapid access to an array of various (hetero)arylated N-containing polyheteroaromatics as new potential bioactive compounds. Full article

Use of a Pictet-Spengler reaction of tryptamine and l-tryptophan methyl ester and subsequent reduction of the nitro group followed by further cyclocondensation with aryl aldehydes and formyl–substituted carboxylic acids, including ferrocene-based components, furnished a series of diastereomeric 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo[2′,3′:3,4]pyrido[1-c]-quinazolines and 5,5b,17,18-tetrahydroindolo[2′,3′:3,4]pyrido[1,2-c]isoindolo[2,1-a]quinazolin-11-(15bH)-ones with the elements of central-, planar and conformational chirality. The relative configuration and the conformations of the novel polycyclic indole derivatives were determined by ¹H- and ¹³C-NMR methods supplemented by comparative DFT analysis of the possible diastereomers. The structure of one of the pentacyclic methyl esters with defined absolute configuration “S” was also confirmed by single crystal X-ray diffraction measurement. Accounting for the characteristic substituent-dependent diastereoselective formation of the products multistep mechanisms were proposed on the basis of the results of DFT modeling. Preliminary in vitro cytotoxic assays of the products revealed moderate-to-significant antiproliferative effects against PANC-1-, COLO-205-, A-2058 and EBC-1 cell lines that proved to be highly dependent on the stereostructure and on the substitution pattern of the pending aryl substituent. Full article

A simple general synthesis of 1-aryl-6-azaisocytosine-5-carbonitriles 4 is described. This method is based on coupling diazonium salts with cyanoacetylcyanamide 2 and then cyclization of the formed 2-arylhydrazono-2-cyanoacetylcyanamides 3. The 6-azaisocytosines 4 were studied with respect to tautomeric equilibrium and the transformation of functional groups, and used in the synthesis of the condensed heterocyclic compounds: Purine isosteric imidazo[2,1-c]-[1,2,4]triazine 8 and the 1,2,4-triazino[2,3-a]quinazolines 9–12. Full article

We previously published a series of 8-methoxypirazolo[1,5-a]quinazolines (PQs) and their 4,5-dihydro derivatives (4,5(H)PQ) bearing the (hetero)arylalkylester group at position 3 as ligands at the γ-aminobutyric type A (GABA_A) subtype receptor. Continuing the study in this field, we report here the design and synthesis of 3-(hetero)arylpyrazolo[1,5-a]quinazoline and 3-(hetero)aroylpyrazolo[1,5-a]quinazoline 8-methoxy substituted as interesting analogs of the above (hetero)arylalkylester, in which the shortening or the removal of the linker between the 3-(hetero)aryl ring and the PQ was performed. Only compounds that are able to inhibit radioligand binding by more than 80% at 10 μM have been selected for electrophysiological studies on recombinant α1β2γ2L GABA_A receptors. Some compounds show a promising profile. For example, compounds 6a and 6b are able to modulate the GABA_AR in an opposite manner, since 6b enhances and 6a reduces the variation of the chlorine current, suggesting that they act as a partial agonist and an inverse partial agonist, respectively. The most potent derivative was 3-(4-methoxyphenylcarbonyl)-8-methoxy-4,5-dihydropyrazolo[1,5-a] quinazoline 11d, which reaches a maximal activity at 1 μM (+54%), and it enhances the chlorine current at ≥0.01 μM. Finally, compound 6g, acting as a null modulator at α1β2γ2L, shows the ability to antagonize the full agonist diazepam and the potentiation of CGS 9895 on the new α+/β− ‘non-traditional’ benzodiazepine site. Full article

The reaction of 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with 3-aryl-2,4-di (ethoxycarbonyl)-5-hydroxy-5-methylcyclohexanones in boiling acetic acid leads to the formation of new 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazolines. The mechanism is discussed. The structure of the products was confirmed by means of 1Н и 13С (DEPTQ) NMR, as well as 2D NMR (NOESY, 1Н–13С HSQC, HMBC). Full article

Efficient metal catalyzed C–H arylation of 8-alkyl-thiazolo[5,4-f]-quinazolin-9-ones was explored for SAR studies. Application of this powerful chemical tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among the potentially active compounds designed through this strategy, FC162 (4c) exhibits nanomolar IC₅₀ values against some kinases, and is the best candidate for the development as a DYRK kinase inhibitor. Full article

A series of indole-aminoquinazolines was prepared via amination of the 2-aryl-4-chloroquinazolines with the 7-amino-2-aryl-5-bromoindoles. It was then evaluated for cytotoxicity in vitro against human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma (C3A), breast adenocarcinoma (MCF-7), and cervical cancer (HeLa) cells. A combination on the quinazoline and indole moieties of a 2-phenyl and 2-(4-fluorophenyl) rings in compound 4b; 2-(4-fluorophenyl) and 3-chlorophenyl rings in compound 4f; or the two 2-(4-fluorophenyl) rings in compound 4g, resulted in significant and moderate activity against the Caco-2 and C3A cell lines. The indole-aminoquinazoline hybrids compounds 4f and 4g induced apoptosis in Caco-2 and C3A cells, and were also found to exhibit moderate (IC₅₀ = 52.5 nM) and significant (IC₅₀ = 40.7 nM) inhibitory activity towards epidermal growth factor receptor (EGFR) against gefitinib (IC₅₀ = 38.9 nM). Molecular docking suggests that 4a–h could bind to the ATP region of EGFR like erlotinib. Full article