- Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1
-
As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cytotoxicity, mainly from off-target cross reactivity. The C-terminal noncatalytic polo-box domain (PBD) of Plk1 has emerged as an attractive target for generating new protein-protein interaction inhibitors. Here, we identified a 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one scaffold that efficiently inhibits Plk1 PBD but not its related Plk2 and Plk3 PBDs. Structure-activity relationship studies led to multiple inhibitors having ≥10-fold higher inhibitory activity than the previously characterized Plk1 PBD-specific phosphopeptide, PLHSpT (Kd ~450 nM). In addition, S-methyl prodrugs effectively inhibited mitotic progression and cell proliferation and their metabolic stability was determined. These data describe a novel class of small-molecule inhibitors that offer a promising avenue for future drug discovery against Plk1-addicted cancers.
- Alverez, Celeste N.,Park, Jung-Eun,Toti, Kiran S.,Xia, Yangliu,Krausz, Kristopher W.,Rai, Ganesha,Bang, Jeong K.,Gonzalez, Frank J.,Jacobson, Kenneth A.,Lee, Kyung S.
-
-
Read Online
- Application of Deep Eutectic Solvents in the Synthesis of Substituted 2-Mercaptoquinazolin-4(3H)-Ones: A Comparison of Setected Green Chemistry Methods
-
In this study, deep eutectic solvents (DESs) were used as green and eco-friendly media for the synthesis of substituted 2-mercaptoquinazolin-4(3H)-ones from different anthranilic acids and aliphatic or aromatic isothiocyanates. A model reaction on anthranilic acid and phenyl isothiocyanate was porformed in 20 choline chloride-based DESs at 80 °C to find the best solvent. Based on the product yield, choline chloride-urea (1:2) DES was found to be the most effective, while DESs acted both as solvents and catalysts. Desired compounds were prepared with moderate to good yields using stirring, microwave-assisted, and ultrasound-assisted synthesis. Significantly, higher yields were obtained with mixing and ultrasonication (16-76%), while microwave-induced synthesis showed lower effectiveness (13-49%). The specific contribution of this research is the use of DESs in combination with the above-mentioned green techniques for the synthesis of a wide range of derivatives. The structures of the synthesized compounds were confirmed by1H and13C NMR spectroscopy.
- Jerkovi?, Igor,Komar, Mario,Kraljevi?, Tatjana Gazivoda,Molnar, Maja
-
-
- Design and synthesis of novel quinazolinone-based fibrates as PPARα agonists with antihyperlipidemic activity
-
Aiming to discover new antihyperlipidemic agents, a new set of quinazolinone-fibrate hybrids 9a–r bearing the essential features for peroxisome proliferator-activated receptor-α (PPARα) agonistic activity was synthesized and the structures were confirmed by different spectral data. All the target compounds were screened for their PPARα agonistic activity. Compounds 9o and 9q exhibited potent activity, with EC50 values better than that of fenofibrate by 8.7- and 27-fold, respectively. Molecular docking investigations were performed for all the newly synthesized compounds in the active site of the PPARα receptor to study their interactions and energies in the receptor. Moreover, the antihyperlipidemic and antioxidant activities of compounds 9o and 9q were determined using Triton WR-1339-induced hyperlipidemic rats. Compound 9q exhibited effective hypolipidemic activity in a dose-dependent manner, where it significantly reduced the serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol and increased the level of high-density lipoprotein cholesterol. Furthermore, it possesses a powerful antioxidant profile where it significantly elevated the levels of reduced glutathione as well as the total antioxidant capacity and significantly decreased the malondialdehyde level. The histopathological studies revealed that compound 9q improved the aortic architecture and hepatic steatosis. These findings support that compound 9q could be a promising lead compound for the development of new antihyperlipidemic agents.
- Hassan, Rasha M.,Ali, Islam H.,Abdel-Maksoud, Mohammed S.,Abdallah, Heba M. I.,El Kerdawy, Ahmed M.,Sciandra, Francesca,Ghannam, Iman A. Y.
-
-
- Design, molecular docking, in vitro, and in vivo studies of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors with potential activity against hepatocellular carcinoma
-
A series of new VEGFR-2 inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against hepatocellular carcinoma (HepG-2 cell line). Compound 29b (IC50 = 4.33 ± 0.2 μg/ml) was found to be the most potent derivative as it has showed to be more active than doxorubicin (IC50 = 4.50 ± 0.2 μg/ml) and 78% of sorafenib activity (IC50 = 3.40 ± 0.25 μg/ml). The inhibitory profiles against VEGFR-2 were also assessed for the most promising candidates (16b, 20c, 22b, 24a, 24b, 28c, 28e, 29a, 29b and 29c). Compounds 29b, 29c and 29a exhibited potent inhibitory activities towards VEGFR-2 at IC50 values of 3.1 ± 0.04, 3.4 ± 0.05 and 3.7 ± 0.06 μM, respectively, comparing sorafenib (IC50 = 2.4 ± 0.05 μM). Furthermorer, compound 29b induced apoptosis and arrested the cell cycle growth at G2/M phase. Additionally, in vivo antitumor experiments revealed that compounds 29b and 29c have significant tumor growth inhibition. The test of immuno-histochemical expression of activated caspase-3 revealed that there is a time-dependent increase in cleaved caspase-3 protein expression upon exposure of HepG-2 cells to compound 29b. Moreover, the fibroblastic proliferative index test revealed that compound 29b could attenuate liver fibrosis. Docking studies also supported the results concluded from the biological screening via prediction of the possible binding interactions of the target compounds with VEGFR-2 active sites using the crystal structure of VEGFR-2 downloaded from the Protein Data Bank, (PDB ID: 2OH4) using Discovery Studio 2.5 software. Further structural optimization of the most active candidates may serve as a useful strategy for getting new lead compounds in search for powerful and selective antineoplastic agents.
- Eissa, Ibrahim.H.,Ibrahim, Mohammed K.,Metwaly, Ahmed M.,Belal, Amany,Mehany, Ahmed B.M.,Abdelhady, Alsayed A.,Elhendawy, Mostafa A.,Radwan, Mohamed M.,ElSohly, Mahmoud A.,Mahdy, Hazem A.
-
-
- Anti-HIV and Antibacterial Activities of Novel 2-(3-Substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones
-
Abstract: In the present study, we have synthesized a series of novel 2-(3-substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones by the reaction of 3-(substituted)-2-hydrazino-quinazoline-4(3H)-ones with phthalic anhydride. The starting material 3-(substituted)-2-hydrazino-quinazolin-4(3H)-ones were synthesized from various primary amines. All the synthesized compounds were screened for their antitubercular, anti-HIV and antibacterial activity against different gram positive and gram negative strains by agar dilution method. Among the test compounds, 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-dione (QCT7) shown most potent antibacterial activity against E. coli, and S. aureus with the MIC of 3 μg/mL. The compound QCT7 exhibited the antitubercular activity with the MIC of 25 μg/mL and anti-HIV activity with the EC50 of 43.68 μM against HIV1 and HIV2 and offers potential lead for further optimization and development to new antitubercular and anti-HIV agents. The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities and are new scaffolds for antimicrobial activity.
- Sulthana,Chitra,Alagarsamy,Saravanan,Solomon, V. Raja
-
p. 112 - 121
(2021/04/05)
-
- Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
-
Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26b, 29a, 29b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 μM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC50 value of 2.5 ± 0.04 μM, almost equal to that of sorafenib (IC50 = 2.4 ± 0.05 μM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities.
- Belal, Amany,Eissa, Ibrahim H.,El-Gamal, Kamal M. A.,El-Sharkawy, Abdou,Elhendawy, Mostafa A.,Elsohly, Mahmoud A.,Ibrahim, Mohammed K.,Mahdy, Hazem A.,Mehany, Ahmed B. M.,Metwaly, Ahmed M.,Radwan, Mohamed M.
-
-
- Anti-HIV, Antitubercular and Antibacterial Activities of Novel 3-(Substituted Quinazolinylamino)-2-phenyl quinazolin-4(3H)ones
-
In the present study, we have synthesized a series of novel 2-phenyl-3-(substituted quinazolinylamino)quinazolin-4(3H)-ones by the reaction of 3-(substituted)-2-hydrazinoquinazoline-4(3H)-ones with 2-phenyl-3,1-benzoxazin-4-one. The starting material 3-(substituted)-2-hydrazino-quinazolin-4(3H)-ones were synthesized from various primary amines. All the synthesized compounds were screened for their antitubercular, anti-HIV and antibacterial activity against different Gram-positive and Gram-negative strains by agar dilution method. Among the test compounds, 3-(4-nitrophenyl)-2-(4-oxo-2-phenylquinazolin-3(4H)-ylamino)quinazolin-4(3H)-one (BQZ6) and 3-(4-chlorophenyl)-2-(4-oxo-2-phenylquinazolin-3(4H)-ylamino)quinazolin-4(3H)-one (BQZ7) shown most potent antibacterial activity against E. coli, P. aeruginosa and S. aureus with the MIC of 3 μg/mL. The compound BQZ7 exhibited the antitubercular activity with the MIC of 25 μg/mL and anti-HIV activity with the MIC of 35.4 μg/mL against HIV1 and HIV2 and offers potential lead for further optimization and development to new antitubercular and anti-HIV agents. The results from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities and are new scaffolds for antimicrobial activity.
- Sulthana,Chitra,Alagarsamy
-
p. 281 - 286
(2020/01/08)
-
- Synthesis, molecular modeling and anti-cancer evaluation of a series of quinazoline derivatives
-
Quinazolines were surveyed as biologically relevant moieties against different cancer cell lines, so in the present study, we analyzed novel derivatives as target-oriented chemotherapeutic anti-cancer drugs. A series of 3-substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a-e were synthesized via the reaction of 2-aminobenzoic acid (1) with isothiocyanate derivatives 2a-e. S-alkylation and S-glycosylation were carried via the reaction of 4a-e with alkyl halides and α-glycopyranosyl bromides 7a,b under anhydrous alkaline and glycoside conditions, respectively. The S-alkylated and S-glycosylated structures, and not that of the N-alkylated and N-glycosylated isomers, have been selected for the products. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The S site of alkylation and glycosylation were determined from the 1H, 13C heteronuclear multiple-quantum coherence (HMQC) experiments. All derivatives were subjected to molecular docking calculations, which selected some derivatives (5n, 8c, 8g, 9c, and 9a) as promising ones based on their excellent binding affinities towards the EGFR tyrosine kinase molecular target. The in vitro cytotoxic activity against MCF-7 and HepG2 cell lines showed effective anti-proliferative activity of the analyzed derivatives with lower IC50 values especially 9a with IC50 = 2.09 and 2.08 μM against MCF-7 and HepG2, respectively, and their treatments were safe against the normal cell line Gingival mesenchymal stem cells (GMSC). Moreover, RT-PCR reaction investigated the apoptotic pathway for the compound 9a, which activated the P53 genes and its related genes. So, further work is recommended for developing it as a chemotherapeutic drug.
- Khodair, Ahmed I.,Alsafi, Mona A.,Nafie, Mohamed S.
-
-
- Eco-friendly rapid synthesis of 3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones in choline chloride based deep eutectic solvent
-
A series of 3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones and 6-iodo-3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones were synthesized in choline chloride/urea deep eutectic solvent. Substituted 2-mercapto-4(3H)-quinazolinones were synthesized from anthranilic acid or 5-iodoanthranilic acid and appropriate isothiocyanates in good to excellent yields. Isolation of final product was easy and required no further purification. Synthesis of these compounds was rapid, selective, and catalyst free, while preparation of deep eutectic solvent was easy, components are readily available, cheap, and environmentally friendly.
- Molnar, Maja,Klenkar, Jelena,Tarnai, Tena
-
p. 1040 - 1045
(2017/05/25)
-
- Nanomagnetically modified polyphosphoric acid (NiFe2O4@SiO2-PPA): An efficient, fast, and reusable catalyst for the synthesis of 2-thioxoquinazolinones under solvent-free conditions
-
Polyphosphoric acid functionalized silica-coated magnetic nanoparticles with core-shell structure (NiFe2O4@SiO2-PPA) has been used as a magnetically recyclable green catalyst for the one-pot three-component synthesis of 2-thioxoquinazolinones by the reaction of isatoic anhydride, primary amines and thiourea under neat conditions. The catalyst is readily recovered by simple magnetic decantation and can be recycled five times with no significant loss of catalytic activity.
- Eshghi, Hossein,Khojastehnezhad, Amir,Moeinpour, Farid,Bakavoli, Mehdi,Zeinabi, Nafiseh,Allameh, Sadegh
-
p. 7915 - 7924
(2015/04/16)
-
- Synthesis of new 2-(N'-Allylidene-hydrazino)quinazolinones and 2-(4,5-Dihydropyrazolyl)-quinazolinones and their antimicrobial and antifungal activity screening
-
Novel 2-[N'-(1,3-disubstituted-phenyl)allylidene]hydrazine-3-ethyl-3H- quinazolin-4-one (8) and 2-(3,5-disubstituted-phenyl-4,5-dihydropyrazol- 1-yl)-3-ethyl-3H-quinazolin-4-one (9) compounds have been prepared and tested for antibacterial and antifungal activities. 1H NMR, 13C NMR, elemental analysis and mass spectroscopy methods have been used to identify molecular structures of the newly synthesized compounds. For screening antibacterial and antifungal activities of the new compounds, minimum inhibitory concentration (MIC) values were evaluated against the Staphylococcus aureus, Escherichia. coli, Pseudomonas aeruginosa, Enterococcus faecalis, Candida albicans, Candida parapsilosis and Candida krusei using microdilution broth method. Compounds 8a-8h exhibited the best antibacterial activity against E. faecalis.
- Saygili, Nezire,Ekizoglu, Melike,Erdogdu, Ceren
-
p. 3197 - 3203
(2014/07/22)
-
- Synthesis of novel quinazoline-4-one derivatives and their acyclonucleoside analogs
-
A number of quinazolin-4-one derivatives were synthesized. Reaction of the 2-hydrazonoquinazoline-4-one derivatives with aldoses afforded the corresponding sugar hydrazones which on treatment with ferric chloride to afford the corresponding acyclic nucleoside analogues.
- Zahran, Magdy A.-H.,Ali, Omar M.,Zeid, Ibrahim F.,Rageb, Elham
-
experimental part
p. 2121 - 2124
(2012/08/28)
-
- An efficient one-pot multicomponent synthesis of 2,3-dihydro-3-alkyl/aryl- 2-thioxoquinazolin-4(1 H)-ones under solvent-free conditions
-
A series of 2,3-dihydro-3-alkyl/aryl-2-thioxoquinazolin-4(1H)-one is prepared by one-pot multicomponent reaction of anthranilic acid, S,S-dimethyl trithiocarbonate and aliphatic/aromatic amine under solvent-free conditions. Georg Thieme Verlag Stuttgart New York.
- Devi, Nepram Sushuma,Singh, Sarangthem Joychandra,Singh, Okram Mukherjee
-
p. 2111 - 2115
(2012/11/07)
-
- Reaction of primary alkylamines, heterocumulenes, and isatoic anhydride, catalyzed by magnetic Fe3O4 nanoparticles in H 2O
-
An efficient protocol for the one-pot reaction of isatoic anhydride (=1,2-dihydro-4H-3,1-benzoxazine-2,4-dione), primary alkylamines, and heterocumulenes (isothiocyanates and isocyanates) in H2O catalyzed by magnetically recoverable Fe3O4 nanoparticles is described. Copyright
- Yavari, Issa,Beheshti, Saeideh
-
experimental part
p. 1825 - 1830
(2011/12/02)
-
- Synthesis and Antibacterial Activity of 2-thio>-3-aryl(or alkyl)-6,8-disubstituted-4(3H)-quinazolinones
-
Synthesis of 47 new 2-thio>-3-aryl(or alkyl)-6,8-disubstituted-4(3H)-quinazolinones, 2-6, from the corresponding 2-thio-4(3H)-quinazolinones, 1, has been described.Fifteen of them were screened for their antibacterial activity by t
- Lakhan, Ram,Rai, Babban J.
-
p. 384 - 386
(2007/10/02)
-