共查询到20条相似文献,搜索用时 167 毫秒
1.
Zheng Li Chunxia Liu Wei Shi Xingguang Cai Yuxuan Dai Chen Liao Wenlong Huang Hai Qian 《Bioorganic & medicinal chemistry》2018,26(3):703-711
The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50?=?7.9?nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE?=?0.32) and ligand lipophilicity efficiency (LLE?=?6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration. 相似文献
2.
Takashi Nakahata Kazuyuki Tokumaru Yoshiteru Ito Naoki Ishii Masaki Setoh Yuji Shimizu Toshiya Harasawa Kazunobu Aoyama Teruki Hamada Masakuni Kori Kazuyoshi Aso 《Bioorganic & medicinal chemistry》2018,26(8):1598-1608
G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7-positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H-pyrazole derivative 17 (GPR52 EC50?=?21?nM, Emax?=?103%, logD?=?2.21, Solubility at pH 6.8?=?21?μg/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice. 相似文献
3.
Ren Sheng Liu Yang Yanchun Zhang Enming Xing Rui Shi Xiaoan Wen Heyao Wang Hongbin Sun 《Bioorganic & medicinal chemistry letters》2018,28(15):2599-2604
GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50?=?93?nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure–activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications. 相似文献
4.
Shuang Guo Mingshuo Xu Qi Guo Fuqiang Zhu Xiangrui Jiang Yuanchao Xie Jingshan Shen 《Bioorganic & medicinal chemistry》2019,27(5):748-759
To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a–8c with similar EC50 values (0.20–0.22?μM) comparative to that of sofosbuvir (EC50?=?0.18?μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50?=?7.3?μM) and S-29b (EC50?=?19.5?μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents. 相似文献
5.
Ricardo Gallardo-Macias Pradeep Kumar Mark Jaskowski Todd Richmann Riju Shrestha Riccardo Russo Eric Singleton Matthew D. Zimmerman Hsin Pin Ho Véronique Dartois Nancy Connell David Alland Joel S. Freundlich 《Bioorganic & medicinal chemistry letters》2019,29(4):601-606
The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC?=?0.019–0.20?μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC50?=?40–>120?μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC?=?0.019?μM) and Vero cell cytotoxicity (CC50?>?120?μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules. 相似文献
6.
Kazuhito Harada Jun Mizukami Sho Kadowaki Isamu Matsuda Takashi Watanabe Yasuhiro Oe Yoshitoshi Kodama Kenta Aoki Katsunori Suwa Sumiaki Fukuda Shinji Yata Takashi Inaba 《Bioorganic & medicinal chemistry letters》2018,28(7):1228-1233
Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50?=?4?nM) with no CYP inhibitory activity (IC50 >10?μM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats. 相似文献
7.
Aigui Zhang Jingya Zhou Ke Tao Taiping Hou Hong Jin 《Bioorganic & medicinal chemistry letters》2018,28(18):3042-3045
Sixteen novel pyrazole carboxamides with diarylamines scaffold were designed, synthesized and characterized in detail via 1H NMR, 13C NMR and ESI-HRMS. Preliminary bioassays showed that some of the target compounds exhibited good antifungal activity against Rhizoctonia solani, Fusarium oxysporum, Phytophthora infestans and Fusarium graminearum. Among them, compound 1c exhibited the highest antifungal activities against R. solani in vitro with EC50 value of 0.005?mg/L, superior to the commercially available fungicide fluxapyroxad (EC50?=?0.033?mg/L). And compound 1c (IC50?=?0.034?mg/L) showed higher inhibition abilities against succinate dehydrogenase than fluxapyroxad (IC50?=?0.037?mg/L). This study suggests that compound 1c could be regarded as a potential succinate dehydrogenase inhibitor. 相似文献
8.
Min Jung Choi Eun Joo Roh Wooyoung Hur So Ha Lee Taebo Sim Chang-Hyun Oh Sun-Hwa Lee Jong Seung Kim Kyung Ho Yoo 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3761-3765
A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC50 values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC50?=?<0.00050?μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC50?=?<0.00050, 0.025, and 0.050?μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI50?=?0.10?μM) related to acute myeloid leukemia (AML). 相似文献
9.
Dagui Zhou Dandan Xie Fangcheng He Baoan Song Deyu Hu 《Bioorganic & medicinal chemistry letters》2018,28(11):2091-2097
A new concise and facile method was explored to synthesize a series of novel chalcone derivatives containing a purine and benzenesulfonamide moiety and their antiviral properties were evaluated against TMV and CMV. Biological assays indicated that several of the derivatives exhibited significant anti-TMV and anti-CMV activities in vivo. In particular, compound d2 displayed excellent inactivating activity against TMV, with the EC50 value of 51.65?μg/mL, which was better than that of ribavirin (150.45?μg/mL). Molecular docking showed that there are four hydrogen bonds between compound d2 and TMV coat protein (TMV-CP). Compound d2 demonstrated strong binding capacity to TMV-CP with Ka?=?1.58?×?105?L/mol and Kd?=?12.16?μM. These findings indicated that chalcone derivatives are worthy of further research and development as templates for new antiviral agents. 相似文献
10.
Yan-Ting Wang Tian-Qi Shi Hai-Liang Zhu Chang-Hong Liu 《Bioorganic & medicinal chemistry》2019,27(3):502-515
Tubulin-targeting drugs have increasingly become the focus of anticancer drugs research. Twenty-five novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives were synthesized and evaluated for bioactivity as potential tubulin polymerization inhibitors. Among them, compound 30 showed the most excellent inhibition against tubulin assembly (IC50?=?1.52?μM) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC50?=?0.15, 0.21, 0.33 and 0.17?μM, respectively for A549, Hela, HepG2 and MCF-7). It could also validly induce A549 cell apoptosis, cause cell cycle arrest in G2/M phase and disrupt the cellular microtubule network. These results, along with molecular docking data, provided an important basis for further optimization of compound 30 as a potential anticancer agent. 相似文献
11.
Rita Fuerst Jun Yong Choi Anna M. Knapinska Lyndsay Smith Michael D. Cameron Claudia Ruiz Gregg B. Fields William R. Roush 《Bioorganic & medicinal chemistry》2018,26(18):4984-4995
A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20?min, kinetic solubility higher than 20?μM, and a permeability coefficient greater than 20?×?10?6?cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (Cmax?=?56.8?μM, T1/2 (plasma)?=?3.0?h, Cl?=?0.23?mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model. 相似文献
12.
Qing Song Yan Li Zhongcheng Cao Hongyan Liu Chaoquan Tian Ziyi Yang Xiaoming Qiang Zhenghuai Tan Yong Deng 《Bioorganic & medicinal chemistry》2018,26(23-24):6115-6127
A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC50?=?0.56?μM and 5.12?μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ1–42 aggregation (IC50?=?3.05?μM) and Cu2+-induced Aβ1–42 aggregation (71.7% at 25.0?μM), and displayed significant disaggregation ability to self- and Cu2+-induced Aβ1–42 aggregation fibrils (75.2% and 77.2% at 25.0?μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD. 相似文献
13.
Allan M. Prior Xufen Yu Eun-Jung Park Tamara P. Kondratyuk Yan Lin John M. Pezzuto Dianqing Sun 《Bioorganic & medicinal chemistry letters》2017,27(24):5393-5399
In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50?=?1.61?μM; 21, IC50?=?3.05?μM; and 27, IC50?=?3.34?μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR?=?8.34, CD?=?2.75?μM), while 7 showed the most potent CD value of 1.12?μM. A dual acting compound 24 showed aromatase inhibition (IC50?=?9.00?μM) as well as QR1 induction (CD?=?5.76?μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group. 相似文献
14.
Yu-Shun Yang Mi-Mi Su Xu-Ping Zhang Qi-Xing Liu Zhen-Xiang He Chen Xu Hai-Liang Zhu 《Bioorganic & medicinal chemistry letters》2018,28(19):3182-3186
By recruiting the important moiety from Shikonin, a series of novel oxoindoline derivatives S1–S20 have been synthesized for inhibiting H. pylori urease. The most potent compound S18 displayed better activity (IC50?=?0.71?μM; MIC?=?0.48?μM) than the positive controls AHA (IC50?=?17.2?μM) and Metronidazole (MIC?=?31.3?μM). With low cytotoxicity, it showed considerable potential for further development. Docking simulation revealed the possible binding pattern of this series. 3D QSAR model was built to discuss SAR and give useful hints for future modification. 相似文献
15.
Wenwen Liu Huan Wang Xiaokang Li Yixiang Xu Jian Zhang Wei Wang Qi Gong Xiaoxia Qiu Jin Zhu Fei Mao Haiyan Zhang Jian Li 《Bioorganic & medicinal chemistry》2018,26(12):3117-3125
Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodone-tacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT1A agonist activities (1d, EC50?=?0.36?±?0.08?nM; 2a, EC50?=?0.58?±?0.14?nM) and 5-HT reuptake inhibitory activities (1d, IC50?=?20.42?±?6.60?nM; 2a, IC50?=?22.10?±?5.80?nM). In addition, they showed moderate ChE inhibitory activities (1d, AChE IC50?=?1.72?±?0.217?μM, BuChE IC50?=?0.34?±?0.03?μM; 2a, AChE IC50?=?2.36?±?0.34?μM, BuChE IC50?=?0.10?±?0.01?μM). Good multitarget activities with goodt blood-brain barrier permeability of 1d and 2a make them good lead compounds for the further study of depression with cognitive impairment. 相似文献
16.
Zhong-Chang Wang Fa-Qian Shen Meng-Ru Yang Ling-Xia You Li-Zhi Chen Hai-Liang Zhu Ya-Dong Lu Fan-Lei Kong Ming-Hua Wang 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3816-3821
MMP-2/MMP-8 is established as one of the most important metalloenzymes for targeting cancer. A series of dihydropyrazothiazole derivatives (E1–E18) bearing a salicylaldehyde group linked to Pyrazole ring were designed, synthesized, and evaluated for their pharmacological activity as MMP-2/MMP-8 inhibitors. Among them, compound E17 exhibited most potent inhibitory activity (IC50?=?2.80?μM for MMP-2 and IC50?=?5.6?μM for MMP-8), compared to the positive drug CMT-1 (IC50?=?1.29?μM). Compounds (E1–E18) were scrutinized by CoMFA and CoMSIA techniques of Three-dimensional quant. structure-activity relationship (3D-QSAR), as well as a docking simulation. Moreover, treatment with compound E4 could induce MCF-7 cell apoptosis. Overall, the biological profile of E1–E18 may provide a research basis for the development of new agents against cancer. 相似文献
17.
Nan Zheng Jing Pan Qun Hao Yingxia Li Weicheng Zhou 《Bioorganic & medicinal chemistry》2018,26(8):2165-2172
A series of 3-substituted pyrazolopyrimidine derivatives as BTK inhibitors were designed by structure-based drug design and they were synthesized, evaluated by enzyme-based assay and anti-proliferation against Ramos and Raji cells. Most of them displayed good inhibitory activities against both BTK and B-cell lymphoblastic leukemia lines in vitro. Among them, compound 8a exhibited excellent potency (IC50?=?7.95?nM against BTK enzyme, 8.91?μM against Ramos cells and 1.80?μM against Raji cells), with a better hydrophilicity (ClogP?=?3.33). These explorations provided new clues to discover 3-substituted pyrazolopyrimidine derivatives as novel anti-tumor agents. 相似文献
18.
Hyojin Kim Suk Joon Cho Minjin Yoo Seung Kyu Kang Kwang Rok Kim Hwan Hee Lee Jin Sook Song Sang Dal Rhee Won Hoon Jung Jin Hee Ahn Jae-Kyung Jung Kwan-Young Jung 《Bioorganic & medicinal chemistry letters》2017,27(23):5213-5220
A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49?nM and 18?nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 & 32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test. 相似文献
19.
Dong-Su Kim Jaehwan Lee Ashwini M. Londhe Tara Man Kadayat Jeongmin Joo Hayoung Hwang Kyung-Hee Kim Ae Nim Pae Jungwook Chin Sung Jin Cho Heonjoong Kang 《Bioorganic & medicinal chemistry》2018,26(15):4382-4389
In this study, we designed and synthesized several novel “Y”-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6?nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50?=?0.7?nM) shows much more potent activity than S isomer (EC50?=?6.1?nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders. 相似文献
20.
Synthesis and antitumor activity of biotinylated camptothecin derivatives as potent cytotoxic agents
Cheng-Ting Zi Liu Yang Feng-Qing Xu Fa-Wu Dong Rui-Jing Ma Yan Li Jun Zhou Zhong-Tao Ding Zi-Hua Jiang Jiang-Miao Hu 《Bioorganic & medicinal chemistry letters》2019,29(2):234-237
A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 0.13 to 21.53?μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC50?=?0.13–3.31?μM) and compound 18 (IC50?=?0.23–1.48?μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents. 相似文献