5794-88-7Relevant articles and documents
Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease
Yao, Hong,Uras, Giuseppe,Zhang, Pengfei,Xu, Shengtao,Yin, Ying,Liu, Jie,Qin, Shuai,Li, Xinuo,Allen, Stephanie,Bai, Renren,Gong, Qi,Zhang, Haiyan,Zhu, Zheying,Xu, Jinyi
, p. 7483 - 7506 (2021/06/28)
Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3β: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
UiO-66-NH2as an effective solid support for quinazoline derivatives for antibacterial agents against Gram-negative bacteria
Al Blooshi, Afra G.,Al Neyadi, Shaikha S.,Alnaqbi, Mohamed. A.,Nguyen, Ha L.
supporting information, p. 20386 - 20395 (2021/12/02)
Nanomaterials have been widely used as a class of antibacterial drugs. However, the bottlenecks of this class of materials are their significant aggregation and accumulation, as well as toxicity resulting from excessive metal leaching. Metal-organic frameworks (MOFs) have inspired researchers owing to their distinct characteristics of robust architecture and tunable pore structures, which may help overcome the above challenges. We, herein, synthesize UiO-66-NH2 and use it as a solid support for loading quinazoline derivatives that are specifically designed and active against Gram-negative bacteria. The quinazoline derivatives were adsorbed on UiO-66-NH2 nanoparticles to form new UiO-66-NH2-quinazoline formulations which have a large inhibitory zone against Gram-negative bacteria, compared to that of free quinazoline compounds. This work has the potential for increasing antibacterial activity while also broadening the antibacterial range, and thus opens a pathway for new medical applications using MOFs. This journal is
Design and Synthesis of some new 2,4,6-trisubstituted quinazoline EGFR inhibitors as targeted anticancer agents
Abbass, Safinaz E. S.,Allam, Heba Abdelrasheed,Aly, Enayat E.,El Kerdawy, Ahmed M.,Farouk, Ahmed K. B. A. W.,Rashwan, Essam
, (2020/03/17)
The present study describes the synthesis of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines starting from 4-chloro derivative VI via the reaction with either phenolic compounds to obtain VIIa-f, IXa-d, 2-amino-6-(un)substituted benzothiazole to produce VIIIa-c or hydrazine hydrate to give X. Reaction of the hydrazino functionality of X with appropriate acid anhydride, acid chloride or aldehyde affords XIa-c, XIIa-c and XIVa-i, respectively. The target compounds were screened for their efficacy as EGFR inhibitors compared to gefitinib. Compounds eliciting superior EGFR inhibitory activity were further screened for their in vitro cytotoxicity against two human cancer cell lines namely: MCF7 (breast) and A549 (lung), in addition to normal fibroblast cell WI38 relative to gefitinib as a reference. Furthermore, compounds that showed potent inhibitory activity on wild-type EGFR were screened against mutant EGFR and assayed for their cytotoxicity against mutant EGFR-expressing cell lines PC9 and HCC827. The unsubstituted benzothiazol-2-amine VIIa showing superior EGFR inhibition (IC50 = 0.096 μM) and anticancer activity against MCF-7 cell line (IC50 = 2.49 μM) was subjected to cell cycle analysis and apoptotic assay. Moreover, a molecular docking study was performed to investigate the interaction of some representive compounds with the active site of EGFR- TK.
Quinazolinone Compound and Application Thereof
-
Paragraph 0101-0102; 0104, (2020/11/27)
The present invention relates to a series of quinazolinone compounds and applications thereof as PI3Kα inhibitors. In particular, the present invention relates to a compound shown in formula (I) and a tautomer or pharmaceutically acceptable salt thereof.
Quinazoline based 1,3,5-triazine derivatives as cancer inhibitors by impeding the phosphorylated RET tyrosine kinase pathway: Design, synthesis, docking, and QSAR study
Pathak, Prateek,Naumovich, Vladislav,Grishina, Maria,Shukla, Parjanya Kumar,Verma, Amita,Potemkin, Vladimir
, (2019/08/16)
The present research focused on designing a quinazoline skeleton, framed via 1,3,5-triazine derivatives (QBT) through field mapping and alignment studies. The QBT derivatives were synthesized via time- and cost-effective protocol. The 3D-QSAR study, computational physicochemical properties, and ADME calculation of the derivatives were performed to establish the affinity towards the biological system. Molecular docking in the adenosine triphosphate binding site of the RET tyrosine kinase domain (PDB ID: 7IVU) was studied to elucidate vital structural residues necessary for bioactivity. The derivatives were evaluated for anticancer potency against TPC-1 cells (thyroid cancer), MCF-7 cells (breast cancer), and one normal cell line (human foreskin fibroblasts) via 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide assay followed by an in ovo CAM assay. The entire series of derivatives (8a–o) showed mild to significant anticancer potency against the selected cancer cell lines.
Quinazolinone platinum metal complexes: In silico design, synthesis and evaluation of anticancer activity
Sawant, Sanjay D.,Sahu, Megha,Nerkar, Amit G.
, p. 2164 - 2170 (2018/09/10)
Dihydrofolate reductase (DHFR) has been explored as a target for the development of agents for wide variety of human diseases, including cancer, autoimmune and infectious diseases. Several metal complexes are being used in management of cancer. The square planar Pt(II) complex, cis PtCl2(NH3)2 turned out to be even more effective at forcing filamentous growth. Cisplatin is an inorganic heavy metal complex that has activity similar to cell-cycle-phase-nonspecific alkylating agents such as cyclophosphamide and some other Ni and Cu metal complexes. It produces intrastrand DNA cross-link and form DNA adducts, thus inhibiting the synthesis of DNA, RNA and proteins preferentially. in silico Screening of platinum metal complexes was performed by Vlife MDS 4.3 software. In this procedure, selection of molecule, selection of PDB, optimization of PDB and docking of molecules was carried out. Synthesis of metal complexes was done by multi component reaction method. Platinum metal complexes of quinazolinone Schiff bases prioritized by in silico studies were characterized by IR, TLC, NMR, XRD, FESEM and some physico-chemical parameters. Prioritized molecules were further evaluated by in vitro anticancer cell line assay on ten cell lines with adriamycin as standard. The results showed that the platinum metal complexes of qunazolinone Schiff bases can be potential anticancer agents through DHFR inhibitory mechanism.
Quinazoline clubbed 1,3,5-triazine derivatives as VEGFR2 kinase inhibitors: design, synthesis, docking, in vitro cytotoxicity and in ovo antiangiogenic activity
Pathak, Prateek,Shukla, Parjanya Kumar,Kumar, Vikas,Kumar, Ankit,Verma, Amita
, p. 1 - 13 (2018/04/20)
Abstract: A series of quinazoline clubbed 1,3,5-triazine derivatives (QCT) were synthesized and evaluated for their in vitro anticancer activity against HeLa (human cervical cancer), MCF-7 (human breast cancer cell), HL-60 (human promyelocytic leukemia cell), HepG2 (human Hepatocellular carcinoma cell), and one normal cell line HFF (human foreskin fibroblasts). In vitro assay result encouraged to further move towards in ovo anticancer evaluation using chick embryo. The series of QCT derivatives showed higher anticancer and antiangiogenic activity against HeLa and MCF-7 cell lines. In the series, synthetic molecule 8d, 8l, and 8m displayed significant activity. Further, these results substantiated by docking study on VGFR2. SAR study concluded that the potency of drugs depends on the nature of aliphatic substitution and the heterocyclic ring system. Graphical Abstract: [Figure not available: see fulltext.]
Novel quinoline-derived mTOR inhibitors with remarkable enzymatic and cellular activities: Design, synthesis and biological evaluation
Ma, Xiao-Dong,Qiu, Ni,Yang, Bo,He, Qiao-Jun,Hu, Yong-Zhou
, p. 297 - 310 (2016/03/01)
Herein, we reported the preparation and in vitro development of a novel series of quinoline-based mTOR inhibitors, some of which were obtained via introducing a ring-opening strategy. As for enzymatic activity, more than half of these quinoline derivatives exhibited moderate to potent inhibition against mTOR. Among them, six compounds showed IC50 values below 50 nM. In particular, several quinolines exhibited remarkably enhanced anti-proliferative activities against all the three tested tumor cell lines in contrast to the initial lead 9. As a representative in this series, compound 24 demonstrated IC50 values of 0.11, 0.17 and 0.04 μM against HCT-116, PC-3 and MCF-7 cell lines, respectively. Besides, compounds 17 and 24 were identified to be selective over class I PI3Ks. Further Western blot analysis validated the dual inhibition of mTORC1 and mTORC2 as a result of compound 24 treatment in the MCF-7 cell line, which was beneficial for conquering the S6K/IRS1/PI3K negative feedback loop. Moreover, acceptable stability was displayed by compound 17, another representative of this series, in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), as well as rat liver microsome (RLM). By virtue of the favorable biological profiles, several quinolines merit further in vivo investigation.
6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors
Yadav, Rammohan R.,Guru, Santosh K.,Joshi, Prashant,Mahajan, Girish,Mintoo, Mubashir J.,Kumar, Vikas,Bharate, Sonali S.,Mondhe, Dilip M.,Vishwakarma, Ram A.,Bhushan, Shashi,Bharate, Sandip B.
, p. 731 - 743 (2016/08/02)
Isoform-selective inhibition of PI3K-α has been identified as one of the important strategy to discover effective and safer anticancer agents. Herein, we report discovery of ‘quinazoline’ as a new chemotype for isoform-selective PI3K-α inhibitors. The indolyl substituted quinazoline 9u displayed selective inhibition of PI3K-α with IC50value of 0.201?μM with >49.7 over PI3K-β, and δ-isoforms. Quinazoline 9u also inhibited PI3K-γ with IC50value of 0.750 μM (3.7 fold selective for α-versus γ-isoform). The isoform-selective inhibition was also demonstrated at protein-expression level by western-blot analysis in MCF-7 and PC-3?cells. The isoform-selective inhibitor 9u also showed inhibition of phospho-Akt levels in these cells. Quinazoline 9u showed in-vitro cytotoxicity in MCF-7?cells with GI50of 7?μM, which was highly selective for cancer cells, as it was non-toxic to normal cells fR2, HEK293 and hGF (GI50?>?50?μM). Compound 9u at 25?mg/kg dose showed 62 and 37% TGI in Ehrlich Ascites Carcinoma and Ehrlich Solid Tumor mice models. In nutshell, our efforts to identify potent and efficacious PI3K inhibitors resulted in the discovery of a new class of isoform-selective PI3K-α inhibitors possessing promising in-vivo anticancer activity.
QUINAZOLINE-BASED KINASE INHIBITORS
-
Page/Page column 131; 132, (2016/04/26)
The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.
