共查询到20条相似文献,搜索用时 15 毫秒
1.
Navidpour L Shadnia H Shafaroodi H Amini M Dehpour AR Shafiee A 《Bioorganic & medicinal chemistry》2007,15(5):1976-1982
A new type of 1-aryl-5-(4-methylsulfonylphenyl)imidazoles, possessing C-2 alkylthio (SMe or SEt) substituents, were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo anti-inflammatory activity. The compound, 1-(4-bromophenyl)-5-(4-methylsulfonylphenyl)-2-methylthioimidazole (11g), was the most potent and selective COX-2 inhibitor (COX-2 IC50=0.43 microM with no inhibition of COX-1 up to 25 microM) relative to the reference drug celecoxib (COX-2 IC50=0.21 microM with no inhibition of COX-1 up to 25 microM) and also showed very good anti-inflammatory activity compared to celecoxib in carrageenan-induced rat paw edema assay. 相似文献
2.
A group of N-1 and C-3 disubstituted-indole Schiff bases bearing an indole N-1 (R′ = H, CH2Ph, COPh) substituent in conjunction with a C-3 –CHN–C6H4–4-X (X = F, Me, CF3, Cl) substituent were synthesized and evaluated as inhibitors of cyclooxygenase (COX) isozymes (COX-1/COX-2). Within this group of Schiff bases, compounds 15 (R1 = CH2Ph, X = F), 17 (R1 = CH2Ph, X = CF3), 18 (R1 = COPh, X = F) and 20 (R1 = COPh, X = CF3) were identified as effective and selective COX-2 inhibitors (COX-2 IC50’s = 0.32–0.84 μM range; COX-2 selectivity index (SI) = 113 to >312 range). 1-Benzoyl-3-[(4-trifluoromethylphenylimino)methyl]indole (20) emerged as the most potent (COX-1 IC50 >100 μM; COX-2 IC50 = 0.32 μM) and selective (SI >312) COX-2 inhibitor. Furthermore, compound 20 is a selective COX-2 inhibitor in contrast to the reference drug indomethacin that is a potent and selective COX-1 inhibitor (COX-1 IC50 = 0.13 μM; COX-2 IC50 = 6.9 μM, COX-2 SI = 0.02). Molecular modeling studies employing compound 20 showed that the phenyl CF3 substituent attached to the CN spacer is positioned near the secondary pocket of the COX-2 active site, the CN nitrogen atom is hydrogen bonded (N?NH = 2.85 Å) to the H90 residue, and the indole N-1 benzoyl is positioned in a hydrophobic pocket of the COX-2 active site near W387. 相似文献
3.
El-Sayed MA Abdel-Aziz NI Abdel-Aziz AA El-Azab AS Asiri YA Eltahir KE 《Bioorganic & medicinal chemistry》2011,19(11):3416-3424
New arylhydrazone derivatives and a series of 1,5-diphenyl pyrazoles were designed and synthesized from 1-(4-chlorophenyl)-4,4,4-trifuorobutane-1,3-dione 1. The newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw oedema model. Moreover, they were tested for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Some of the new compounds (2f, 6a and 6d) showed a reasonable in vitro COX-2 inhibitory activity, with IC?? value of 0.45 μM and selectivity index of 111.1. A virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Docking study of the synthesized compounds 2f, 6a and 6d into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. 相似文献
4.
Lingzhi Zhang Tantan Bu Xiaobo Bao Tingting Liang Yiran Ge Yungen Xu Qihua Zhu 《Bioorganic & medicinal chemistry letters》2017,27(15):3395-3398
A series of 3H-imidazo [4,5-b] pyridines derivatives were designed and synthesized as selective mTOR inhibitors. The systematic optimization of the molecules resulted in the identification of two compounds 10d and 10n with nanomolar mTOR inhibitory activity and selectivity over PI3Kα. Besides, compounds 10d and 10n demonstrated attractive potency against human breast cancer cells (MCF-7) and human ovarian cancer cell (A2780). 相似文献
5.
Lu X Zhang H Li X Chen G Li QS Luo Y Ruan BF Chen XW Zhu HL 《Bioorganic & medicinal chemistry》2011,19(22):6827-6832
A series of pyridine acyl sulfonamide derivatives (1-24) have been designed and synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among all the compounds, compound 23 displayed the most potent COX-2 inhibitory activity with an IC(50) of 0.8 μM. Antitumor and anti-inflammatory assays indicated that compound 23 owned high antiproliferative activity against B16-F10, HepG2 and MCF-7 cancer cell lines as well as COX-2-derived prostaglandin E(2) (PGE(2)) inhibitory activity of murine macrophage RAW 264.7 cell line with IC(50) values of 2.8, 1.2, 1.8 and 0.15 μM, respectively. Docking simulation was performed to position compound 23 into the COX-2 active site to determine the probable binding model. 相似文献
6.
A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selectivity for COX-2 than Celecoxib both in vitro and in vivo. 相似文献
7.
Lau CK Brideau C Chan CC Charleson S Cromlish WA Ethier D Gauthier JY Gordon R Guay J Kargman S Li CS Prasit P Riendeau D Thérien M Visco DM Xu L 《Bioorganic & medicinal chemistry letters》1999,9(22):3187-3192
A series of 3-heteroaryloxy4-phenyl-2-5H)-furanones were prepared and evaluated for their potency and selectivity as COX-2 inhibitors. This led to the identification of L-778,736 as a potent, orally active and selective inhibitor of the COX-2 enzyme. 相似文献
8.
Sugane T Tobe T Hamaguchi W Shimada I Maeno K Miyata J Suzuki T Kimizuka T Morita T Sakamoto S Tsukamoto S 《Bioorganic & medicinal chemistry》2012,20(1):34-41
To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound. 相似文献
9.
Gilleron P Wlodarczyk N Houssin R Farce A Laconde G Goossens JF Lemoine A Pommery N Hénichart JP Millet R 《Bioorganic & medicinal chemistry letters》2007,17(19):5465-5471
A new series of FTase inhibitors containing a tricyclic moiety--dioxodibenzothiazepine or dibenzocycloheptane--has been designed and synthesized. Among them, dioxodibenzothiazepine 18d displayed significant inhibitory FTase activity (IC(50)=17.3 nM) and antiproliferative properties. 相似文献
10.
A variety of 4-aryl- and 4-alkyl-3-(substituted benzylthio)-4H-1,2,4-triazoles were prepared and evaluated for their bleaching activity by the lettuce seedling test. Among the series of tested compounds, 4-(3-fluorophenyl)-3-(4-trifluoromethylbenzylthio)-4H-1,2,4-triazole (39) exhibited the highest bleaching activity, causing complete bleaching symptoms at 10 microM. In the dark condition, compound 39 inhibited the formation of such carotenoids as beta-carotene, violaxanthin, neoxanthin and lutein, resulting in the formation of zeta-carotene, phytoene, phytofluene and beta-zeacarotene, which were not detected in the untreated control. Treatment by compound 39 at 50 microM resulted in the amount of accumulated zeta-carotene being seven-fold higher than that of phytoene, phytofluene and beta-zeacarotene. These results suggest that compound 39 might have interfered with desaturation, especially zeta-carotene desaturation, during carotenoid biosynthesis. 相似文献
11.
12.
Three novel series of diarylpyrazole 10b-d and triarylpyrazole derivatives 11a-d &12a-d were synthesized through Vilsmier-Haack condition. The structures of prepared compounds were determined through IR, 1H NMR, 13C NMR, Mass spectral and elemental analysis. Docking of the synthesized compounds over COX-2 active site ensure their selectivity. Moreover, the target compounds were evaluated for both in vitro and in vivo inhibitory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and with excellent anti-inflammatory activity. Compounds 11b, 11d and 12b showed the highest anti-inflammatory activity (67.4%, 62.7%, 61.4% respectively), lower ulcerogenic liability (UI = 2.00, 2.75, 3.25 respectively) than indomethacin (UI = 14) and comparable to celecoxib (UI = 1.75) which were confirmed from the histopatholgical study. 相似文献
13.
Razieh Ghodsi Afshin Zarghi Bahram Daraei Mehdi Hedayati 《Bioorganic & medicinal chemistry》2010,18(3):1029-1033
A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-4 quinoline ring. Among the 2,3-diarylquinolines, 2-(4-(methylsulfonyl) phenyl)-3-phenylquinoline-4-carboxylic acid (8) exhibited the highest potency and selectivity for COX-2 inhibitory activity (COX-2 IC50 = 0.07 μM; selectivity index = 687.1) that was more selective than the reference drug celecoxib (COX-2 IC50 = 0.06 μM; selectivity index = 405). A molecular modeling study where 8 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg513, Phe518 and Val523) and the carboxylic acid substituent can interact with Ser530. The structure activity data acquired indicate that the size and nature of the C-4 quinoline substituent are important for COX-2 inhibitory activity. 相似文献
14.
Singh SK Saibaba V Ravikumar V Rudrawar SV Daga P Rao CS Akhila V Hegde P Rao YK 《Bioorganic & medicinal chemistry》2004,12(8):1881-1893
Several 2,3-diaryl pyrazines and quinoxalines with 4-sulfamoyl (SO(2)NH(2))/methylsulfonyl (SO(2)Me)-phenyl pharmacophores have been synthesized and evaluated for the cyclooxygenase (COX-1/COX-2) inhibitory activity. Smaller groups such as methoxy, methyl and fluoro when substituted at/around position-4 of the adjacent phenyl ring, have great impact on the selective COX-2 inhibitory activity of the series. Many potential compounds were obtained from a brief structure-activity relationship (SAR) study. Two of these, compounds 11 and 25 exhibited excellent in vivo activity in the established animal model of inflammation. Since compound 25 possessed an amenable sulfonamide group, two of its prodrugs 48 and 49 were also synthesized. Both of them have excellent in vivo potential, and represent a new class of COX-2 inhibitor. 相似文献
15.
Xinzhou Bi Jieming Li Jiuhui Li Wei Shi Yuxuan Dai Qifei Li Wenjie Zhang Wenlong Huang Hai Qian Cheng Jiang 《Bioorganic & medicinal chemistry》2019,27(13):2813-2821
Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC50 of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC50 of 1.53 μM. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development. 相似文献
16.
Selective inhibition of cyclooxygenase (COX)-2 enzyme is an important achievement when looking for potent anti-inflammatory agents, with fewer gastrointestinal side effects. In this work, a new series of cinnamic acid derivatives, namely hexylamides, have been designed, synthesized and evaluated in human blood for their inhibitory activity of COX-1 and COX-2 enzymes. From this, new structure-activity relationships were built, showing that phenolic hydroxyl groups are essential for both COX-1 and COX-2 inhibition. Furthermore, the presence of bulky hydrophobic di-tert-butyl groups in the phenyl ring strongly contributes for selective COX-2 inhibition. In addition, a correlation with the theoretical log P has been carried out, showing that lipophilicity is particularly important for COX-2 inhibition. Further, a plasma protein binding (PPB) prediction has been performed revealing that PPB seems to have no influence in the activity of the studied compounds. From the whole study, effective selective inhibitors of COX-2 were found, namely compound 9 (IC50 = 3.0 ± 0.3 μM), 10 (IC50 = 2.4 ± 0.6 μM) and 23 (IC50 = 1.09 ± 0.09 μM). Those can be considered starting point hit compounds for further optimization as potential non-steroidal anti-inflammatory drugs. 相似文献
17.
Zarghi A Najafnia L Daraee B Dadrass OG Hedayati M 《Bioorganic & medicinal chemistry letters》2007,17(20):5634-5637
A group of 2,3-diaryl-1,3-thiazolidine-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. 相似文献
18.
J S Carter D J Rogier M J Graneto K Seibert C M Koboldt Y Zhang J J Talley 《Bioorganic & medicinal chemistry letters》1999,9(8):1167-1170
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition. 相似文献
19.
Danielle M. Hurzy Darrell A. Henze Tamara D. Cabalu Kartik Narayan Amanda Heller Andrew J. Cooke 《Bioorganic & medicinal chemistry letters》2017,27(12):2695-2701
A series of substituted indoles were examined as selective inhibitors of tropomyosin-related kinase receptor A (TrkA), a therapeutic target for the treatment of pain. An SAR optimization campaign based on ALIS screening lead compound 1 is reported. 相似文献
20.
Tannaz Zebardast Afshin Zarghi Bahram Daraie Mehdi Hedayati Orkideh G. Dadrass 《Bioorganic & medicinal chemistry letters》2009,19(12):3162-3165
A new group of 3-alkyl-2-aryl-1,3-thiazinan-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-thiazinan-4-one (11a) as a potent (IC50 = 0.06 μM) and selective (selectivity index >285) COX-2 inhibitor. 相似文献