13906-08-6Relevant articles and documents
Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1
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.
, p. 14087 - 14117 (2020)
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.
Design and synthesis of novel quinazolinone-based fibrates as PPARα agonists with antihyperlipidemic activity
Hassan, Rasha M.,Ali, Islam H.,Abdel-Maksoud, Mohammed S.,Abdallah, Heba M. I.,El Kerdawy, Ahmed M.,Sciandra, Francesca,Ghannam, Iman A. Y.
, (2021/12/30)
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.
Anti-HIV and Antibacterial Activities of Novel 2-(3-Substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones
Sulthana,Chitra,Alagarsamy,Saravanan,Solomon, V. Raja
, p. 112 - 121 (2021/04/05)
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.
