- Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation
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A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI50 ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI50 level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC50 values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC50 = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of ?9.80 to ?11.25 kcal/mol compared to ?12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e.
- Abdel-Aziz, Mohamed,Abdel-Aziz, Salah A.,Abdelrahman, Kamal S.,Gouda, Ahmed M.,Marzouk, Adel A.,Wanas, Amira S.,Youssif, Bahaa G. M.
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- Design, synthesis, and biological evaluation of 4-aminopyrimidine or 4,6-diaminopyrimidine derivatives as beta amyloid cleaving enzyme-1 inhibitors
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A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and permeability relative to lead compound 1 (IC50?=?37.4?μM), which was discovered in a previous virtual screening. The po
- Xu, Xiufeng,Peng,Wang, Junjie,Xu, Fengrong,Liang, Lei,Wang, Chao,Niu, Yan,Xu, Ping
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p. 926 - 933
(2019/02/19)
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- Β - secretase enzyme has the function of inhibiting compound, the preparation of the compounds and use thereof
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The invention discloses a compound capable of inhibiting beta-secretase, and a preparation method and application thereof. The structure of the compound is shown in a formula I, formula II or formula III as described in the specification. In the formula I, X is S or NH; R1 is selected from hydrogen and nitro group; R2 and R4 are same or different and independently selected from the group consisting of hydrogen, halogen, nitro group and substituted aryl group; R3 is selected from the group consisting of hydrogen, nitro group, straight-chain and branched-chain alkyl and substituted alkyl groups with a carbon number of 1 to 4, alkylamino or alkyloxy group with a carbon number of 1 to 4 and alkylamido group with a carbon number of 1 to 4; R is located at position 2, 3 or 4 of a benzene ring and selected from the group consisting of hydrogen, straight-chain and branched-chain alkyl and substituted alkyl groups with a carbon number of 1 to 4, alkylamino or alkyloxy group with a carbon number of 1 to 4 and alkylamido group with a carbon number of 1 to 4. In the formula II, R is selected from different substituted aryl groups. In the formula III, R is selected from hydrogen or cyano group. Experiments prove that the compound provided by the invention has good beta-secretase inhibitory activity and has wide application values as a beta-secretase inhibitor.
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Paragraph 0141; 0142
(2018/03/26)
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- 2-Substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and?docking studies
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In this work, a series of 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamide derivatives were developed as β-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. In addition, the selected compounds were tested with affinity (KD) towards BACE-1, blood brain barrier (BBB) permeability and cytotoxicity. The studies revealed that the most potent analog 41 (IC50 = 4.6 μM) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization.
- Yan, Gang,Hao, Lina,Niu, Yan,Huang, Wenjie,Wang, Wei,Xu, Fengrong,Liang, Lei,Wang, Chao,Jin, Hongwei,Xu, Ping
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p. 462 - 475
(2017/06/19)
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