100800-40-6Relevant articles and documents
4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation
Medapi, Brahmam,Suryadevara, Priyanka,Renuka, Janupally,Sridevi, Jonnalagadda Padma,Yogeeswari, Perumal,Sriram, Dharmarajan
, p. 1 - 16 (2015)
Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of antitubercular drug discovery. In the present study, we employed structural optimization of the reported GyrB inhibitor resulting in synthesis of a series of 46 novel quinoline derivatives. The compounds were evaluated for their in vitro Mycobacterium smegmatis GyrB inhibitory ability and Mycobacterium tuberculosis DNA supercoiling inhibitory activity. The antitubercular activity of these compounds was tested over Mtb H37Rv strain and their safety profile was checked against mouse macrophage RAW 264.7 cell line. Among all, three compounds (23, 28, and 53) emerged to be active displaying IC50 values below 1 μM against Msm GyrB and were found to be non-cytotoxic at 50 μM concentration. Compound 53 was identified to be potent GyrB inhibitor with 0.86 ± 0.16 μM and an MIC (minimum inhibitory concentration) of 3.3 μM. The binding affinity of this compound towards GyrB protein was analysed by differential scanning fluorimetry which resulted in a positive shift of 3.3 °C in melting temperature (Tm) when compared to the native protein thereby reacertaining the stabilization effect of the compound over protein.
Noncovalent EGFR T790M/L858R inhibitors based on diphenylpyrimidine scaffold: Design, synthesis, and bioactivity evaluation for the treatment of NSCLC
Chen, Lixue,Deng, Tuo,Li, Lei,Li, Zhen,Ma, Xiaodong,Meng, Qiang,Sun, Huijun,Tang, Zeyao,Tian, Liangliang,Wang, Changyuan,Wang, Tong,Xu, Youjun,Zhang, Yunhao,Zheng, Xu
, (2021/07/06)
A series of diphenylpyrimidine derivatives bearing a hydroxamic acid group was designed and synthesized as noncovalent EGFRT790M/L858R inhibitors to improve the biological activity and selectivity. One of the most promising compound 9d effectively interfered EGFRT790M/L858R binding with ATP and suppressed the proliferation of H1975 cells with IC50 values of 1.097 nM and 0.09777 μM, respectively. Moreover, compound 9d also not only exhibited a high selective index of 43.4 for EGFRT790M/L858R over the wild-type and 10.9 for H1975 cells over A431, but also exhibited low toxicity against the normal HBE cells (IC50 > 20 μΜ). In addition, the action mechanism validated that compound 9d effectively inhibited cell migration and promoted cell apoptosis by blocking cell cycle at G2/M stage. Furthermore, the target dose-dependently downregulated the expression of p-EGFR and arrested the activation of downstream Akt and ERK in H1975. All these studies provide important clues for the discovery of potent noncovalent EGFRT790M/L858R inhibitors.
Synthesis and biological activity of thieno[3,2-d]pyrimidines as potent JAK3 inhibitors for the treatment of idiopathic pulmonary fibrosis
Zhu, Yanming,Zheng, Xu,Wang, Changyuan,Sun, Xiuli,Sun, Huijun,Ma, Tengyue,Li, Yanxia,Liu, Kexin,Chen, Lixue,Ma, Xiaodong
, (2019/12/28)
Idiopathic pulmonary fibrosis (IPF) is a serious and fatal lung disease, with a median survival of only 3–5 years from diagnosis. Janus kinase 3 (JAK3) has a well-established role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune-related pulmonary fibrosis. In this study, through the use of a conformationally-constrained design strategy, a series of thieno[3,2-d]pyrimidines were synthesized as potent JAK3 inhibitors for the treatment of IPF. Among them, the most potent JAK3 inhibitor, namely 8e (IC50 = 1.38 nM), significantly reduced the degree of airsacculitis and fibrosis according to hematoxylin-eosin (HE) staining assay for the lung tissue in the bleomycin (BLM)-induced pulmonary fibrosis mouse model. The clear reduction of the lung collagen deposition by the determination of Masson and hydroxyproline (HYP) content also demonstrated its efficacy in the treatment of fibrosis. In addition, 8e also reduced the expression of the inflammatory markers IL-6, IL-17A, TNF-α and malondialdehyde (MDA) in lung tissue, which indicated its higher anti-inflammatory activity compared with that of the reference agents (nintedanib and gefitinib). Furthermore, it possessed low cytotoxicity against normal human bronchial epithelia (HBE) cells (IC50 > 39.0 μM) and C57BL mice. All these evaluated biological properties suggest that 8e may be a potential JAK3 inhibitor for the treatment of IPF.
Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3
Li, Yingxiu,Ye, Tianyu,Xu, Le,Dong, Yuhong,Luo, Yong,Wang, Chu,Han, Yufei,Chen, Ke,Qin, Mingze,Liu, Yajing,Zhao, Yanfang
, (2019/08/12)
Hybridization strategy is an effective strategy to obtain multi-target inhibitors in drug design. In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. All compounds were tested for the inhibition of JAK2 and FLT3 enzymes, of which, compounds with potent enzyme activities were assayed for antiproliferative activities against three cancer cell lines (HEL, MV4-11, and HL60). The structure-activity relationship studies were conducted through variations in two regions, the “A” phenyl ring and “B” phenyl ring. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC50 = 27 nM, FLT3 IC50 = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G1/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor.
Identification of highly potent BTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma
Ge, Yang,Wang, Changyuan,Song, Shijie,Huang, Jiaxin,Liu, Zhihao,Li, Yongming,Meng, Qiang,Zhang, Jianbin,Yao, Jihong,Liu, Kexin,Ma, Xiaodong,Sun, Xiuli
, p. 1847 - 1857 (2017/12/04)
The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors.
Synthesis and biological evaluation of morpholine-substituted diphenylpyrimidine derivatives (Mor-DPPYs) as potent EGFR T790M inhibitors with improved activity toward the gefitinib-resistant non-small cell lung cancers (NSCLC)
Song, Zhendong,Huang, Shanshan,Yu, Haiqing,Jiang, Yu,Wang, Changyuan,Meng, Qiang,Shu, Xiaohong,Sun, Hunjun,Liu, Kexin,Li, Yanxia,Ma, Xiaodong
, p. 329 - 339 (2017/04/11)
Potential new EGFRT790M inhibitors comprised of structurally modified diphenylpyrimidine derivatives bearing a morpholine functionality (Mor-DPPYs) were used to improve the activity and selectivity of gefitinib-resistant non-small cell lung cancer (NSCLC) treatment. This led to the identification of inhibitor 10c, which displayed high activity against EGFRT790M/L858R kinase (IC50?=?0.71?nM) and repressed H1975?cell replication harboring EGFRT790M mutations at a concentration of 0.037?μM. Inhibitor 10c demonstrated high selectivity (SI?=?631.9) for T790M-containing EGFR mutants over wild type EGFR, suggesting that it will cause less side effects. Moreover, this compound also shows promising antitumor efficacy in a murine EGFRT790M/L858R-driven H1975 xenograft model without affecting body weight. This study provides new potential lead compounds for further development of anti-NSCLC drugs.
Discovery of biphenyl-based VEGFR-2 inhibitors. Part 3: Design, synthesis and 3D-QSAR studies
Lu, Wen,Li, Pengfei,Shan, Yuanyuan,Su, Ping,Wang, Jinfeng,Shi, Yaling,Zhang, Jie
, p. 1044 - 1054 (2015/03/04)
VEGFR-2 plays an essential role in angiogenesis and is a central target for anticancer drug discovery. In order to develop novel VEGFR-2 inhibitors, we designed and synthesized 33 biphenyl amides based on our previously reported lead compound. The biological results indicated that four compounds (18b, 20e, 20h and 20j) are potent VEGFR-2 inhibitors which are comparable to positive control. Compound 18b displayed the most potent VEGFR-2 inhibition with IC50 value of 2.02 nM. Moreover, it exhibited promising antiproliferative activity against MCF-7 and SMMC-7721 cells with IC50 values of 1.47 μM and 5.98 μM, respectively. Molecular docking and 3D-QSAR studies were also carried out. The results indicated that these biphenyl amides could serve as promising leads for further optimization as novel VEGFR-2 inhibitors.
Design, synthesis and biological evaluation of pyridin-3-yl pyrimidines as potent Bcr-Abl inhibitors
Pan, Xiaoyan,Dong, Jinyun,Gao, Hongping,Wang, Fang,Zhang, Yanmin,Wang, Sicen,Zhang, Jie
, p. 592 - 599 (2014/05/06)
A series of pyridin-3-yl pyrimidines was synthesized and evaluated for their Bcr-Abl inhibitory and anticancer activity. The preliminary results indicated that some compounds were promising anticancer agents. Compounds A2, A8, and A9 exhibited potent Bcr-Abl inhibitory activity, suggesting that aniline containing halogen substituents might be important for biological activity. Molecular docking was carried out to investigate the binding mode of them with Bcr-Abl. Details of synthesis and SAR studies of these compounds are described. A series of phenylaminopyrimidines was designed and synthesized as potent Bcr-Abl inhibitors. The screening of these rationally designed compounds for antitumor activity had identified three candidate leads which could be further optimized to improve the anticancer activities.
Design, synthesis and biological activities of Nilotinib derivates as antitumor agents
Pan, Xiaoyan,Wang, Fang,Zhang, Yanmin,Gao, Hongping,Hu, Zhigang,Wang, Sicen,Zhang, Jie
, p. 2527 - 2534 (2013/06/26)
A novel class of Nilotinib derivatives, B1-B20, were synthesized in high yields using various substituted anilines. All the title compounds were evaluated for their inhibitory activities against Bcr-Abl and antiproliferative effects on human leukemia cell (K562). The pharmacological results indicated that some compounds exhibited promising anticancer activity. In particular, compound B14 containing tertiary amine side chain exhibited Bcr-Abl inhibitory activity similar to that of Nilotinib. It was suggested that the introduction of the tertiary amine moiety could improve Bcr-Abl inhibitory activity and antitumor effects.
2, 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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Page/Page column 136, (2012/05/20)
The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.
