- Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation
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Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed,
- Abdallah, Abdallah E.,Eissa, Sally I.,Al Ward, Maged Mohammed Saleh,Mabrouk, Reda R.,Mehany, Ahmed B.M.,El-Zahabi, Mohamed Ayman
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- Synthesis and biological evaluation of honokiol derivatives bearing 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3h)-ones as potential viral entry inhibitors against sars-cov-2
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The 2019 coronavirus disease (COVID-19) caused by SARS-CoV-2 virus infection has posed a serious danger to global health and the economy. However, SARS-CoV-2 medications that are specific and effective are still being developed. Honokiol is a bioactive component from Magnoliae officinalis Cortex with damp-drying effect. To develop new potent antiviral molecules, a series of novel honokiol analogues were synthesized by introducing various 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones to its molecule. In a SARS-CoV-2 pseudovirus model, all honokiol derivatives were examined for their antiviral entry activities. As a result, 6a and 6p demonstrated antiviral entry effect with IC50 values of 29.23 and 9.82 μM, respectively. However, the parental honokiol had a very weak antiviral activity with an IC50 value more than 50 μM. A biolayer interfero-metry (BLI) binding assay and molecular docking study revealed that 6p binds to human ACE2 protein with higher binding affinity and lower binding energy than the parental honokiol. A competitive ELISA assay confirmed the inhibitory effect of 6p on SARS-CoV-2 spike RBD’s binding with ACE2. Importantly, 6a and 6p (TC50 > 100 μM) also had higher biological safety for host cells than honokiol (TC50 of 48.23 μM). This research may contribute to the discovery of potential viral entrance inhibitors for the SARS-CoV-2 virus, although 6p’s antiviral efficacy needs to be validated on SARS-CoV-2 viral strains in a biosafety level 3 facility.
- Bai, Li-Ping,Guo, Yong,Jiang, Zhi-Hong,Liu, Jia-Zheng,Meng, Jie-Ru,Xu, Ting,Zheng, Zhi-Yuan
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- Discovery of 1,3,4-oxadiazole derivatives as potential antitumor agents inhibiting the programmed cell death-1/programmed cell death-ligand 1 interaction
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Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by small-molecule inhibitors is emerging cancer immunotherapy. A series of novel 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for
- Fang, Lincheng,Tian, Jiping,Zhang, Kaixuan,Zhang, Xiaoyi,Liu, Yingqiao,Cheng, Zhibo,Zhou, Jinpei,Zhang, Huibin
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- Discovery of 3,5-dimethylisoxazole derivatives as novel, potent inhibitors for bromodomain and extraterminal domain (BET) family
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Bromodomain and extra-terminal (BET) is a promising therapeutic target for various hematologic cancers. We used the BRD4 inhibitor compound 13 as a lead compound to develop a variety of compounds, and we introduced diverse groups into the position of the compound 13 orienting toward the ZA channel. A series of compounds (14–23, 38–41, 43, 47–49) bearing triazolopyridazine motif exhibited remarkable BRD4 protein inhibitory activities. Among them, compound 39 inhibited BRD4(BD1) protein with an IC50 of 0.003 μM was superior to lead compound 13. Meanwhile, compound 39 possess activity, IC50 = 2.1 μM, in antiproliferation activity against U266 cancer cells. On the other hand, compound 39 could arrest tumor cells into the G0/G1 phase and induce apoptosis, which was consistent with its results in inhibiting cell proliferation. Biological and biochemical data suggest that BRD4 protein might be a therapeutic target and that compound 39 is an excellent lead compound for further development.
- Fang, Lincheng,Hu, Zhaoxue,Yang, Yifei,Chen, Pan,Zhou, Jinpei,Zhang, Huibin
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supporting information
(2021/04/15)
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- Design and synthesis of tetrahydropyridopyrimidine derivatives as dual GPR119 and DPP-4 modulators
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Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC50 = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 μM. Furthermore, the blood glucose AUC0-2h of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators.
- Fang, Yuanying,Zhang, Shaokun,Wu, Wenting,Liu, Yanhua,Yang, Juan,Li, Yuyuan,Li, Min,Dong, Huanhuan,Jin, Yi,Liu, Ronghua,Yang, Zunhua
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- One-potCuAAC synthesis of (1H-1,2,3-triazol-1-yl)methyl-1,3,4/1,2,4-oxadiazoles starting from available chloromethyl-1,3,4/1,2,4-oxadiazoles
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The one-pot CuAAC synthesis of (1H-1,2,3-triazol-1-yl)methyl-1,3,4-oxadiazole and (1H-1,2,3-triazol-1-yl)methyl-1,2,4-oxadiazole derivatives via three-component reaction of consequent nucleophilic substitution of chlorine, with azide, and its further “cli
- Pokhodylo, Nazariy T.,Savka, Roman D.,Shyyka, Olga Ya.,Obushak, Mykola D.
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p. 2969 - 2976
(2020/05/25)
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- Design and synthesis of new norfloxacin-1,3,4-oxadiazole hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)
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Toward the search of new antibacterial agents to control methicillin-resistant Staphylococcus aureus (MRSA), a class of new norfloxacin-1,3,4-oxadiazole hybrids were designed and synthesized. Antibacterial activities against drug-sensitive bacteria S. aureus and clinical drug resistant isolates of MRSA were evaluated. Compound 5k exhibited excellent antibacterial activities against S. aureus (MIC: 2 μg/mL) and MRSA1–3 (MIC: 0.25–1 μg/mL). The time-kill kinetics demonstrated that compound 5k had an advantage over commonly used antibiotics vancomycin in killing S. aureus and MRSA. Moreover, compound 5k could inhibit the bacteria and destroy their membranes in a short time, and showed very low cytotoxicity to NRK-52E cells. Some interesting structure-activity relationships (SARs) were also discussed. These results indicated that these norfloxacin-1,3,4-oxadiazole hybrids could be further developed into new antibacterial agents against MRSA.
- Guo, Yong,Xu, Ting,Bao, Chongnan,Liu, Zhiyan,Fan, Jiangping,Yang, Ruige,Qin, Shangshang
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- Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents
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The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.
- Li, Zheng,Chen, Yueming,Zhou, Zongtao,Deng, Liming,Xu, Yawen,Hu, Lijun,Liu, Bing,Zhang, Luyong
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p. 352 - 365
(2019/01/04)
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- Biphenyl heterocyclic derivatives, their preparation and their use as medicaments (by machine translation)
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The present invention relates to a novel biphenyl heterocyclic derivative represented by a general formula (I) and a preparation method thereof and use of a pharmaceutical composition containing the derivative for preparation of a drug for treating diabetes. The biphenyl heterocyclic derivative has extremely excellent hypoglycemic activity in vivo, and excellent in vivo safety and low liver toxicity risk of the compound having such a structure are unexpectedly found, and the novel biphenyl heterocyclic derivative may be used for preventing or treating diabetes.
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Paragraph 0298-0301
(2018/06/21)
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- A oxadiazole compound and its preparation method
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The present invention relates to an oxadiazole compound and a preparation method thereof, wherein the molecular formula of the compound is as the follow, R1 is halogen, hydrogen, C1-C4 alkyl or alkoxy, R2 is halogen, hydrogen or alkyl, and R3 is methylamine, dimethylamine, isopropylamine, propylamine, butylamine, morpholine, piperidine or imidazole. Compared with the oxadiazole compound and the preparation method in the prior art, the oxadiazole compound and the preparation method of the present invention have the following characteristics that: the process is simple, the application range is wide, and the oxadiazole compound is suitable for prevention and control of health pests such as flies, mosquitoes, fleas and the like and agricultural pests such as lissorhoptrus oryzophilus, spodoptera exigua hiibner, mythimna separata (walker) and the like, can be provided for inhibiting growth of insects, especially mosquito larvae, and is an insecticide with an application prospect.
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- Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
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The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
- Li, Zheng,Qiu, Qianqian,Xu, Xue,Wang, Xuekun,Jiao, Lei,Su, Xin,Pan, Miaobo,Huang, Wenlong,Qian, Hai
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supporting information
p. 246 - 257
(2016/03/08)
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- Discovery of novel heteroarylmethylcarbamodithioates as potent anticancer agents: Synthesis, structure-activity relationship analysis and biological evaluation
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A series of new analogs based on the structure of lead compound 10 were designed, synthesized and evaluated for their in vitro anti-cancer activities against four selected human cancer cell lines (HL-60, Bel-7402, SK-BR-3 and MDA-MB-468). Several synthesized compounds exhibited improved anti-cancer activities comparing with lead compound 10. Among them, 1,3,4-oxadiazole analogs 17o showed highest bioactivity with IC50 values of 1.23, 0.58 and 4.29 μM against Bel-7402, SK-BR-3 and MDA-MB-468 cells, respectively. It is noteworthy that 17o has potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cells. The further mechanistic study showed that it induced apoptosis and cell cycle arrest through disrupting spindle assembly in mitotic progression, indicating these synthesized dithiocarbamates represented a novel series of anti-cancer compounds targeting mitosis.
- Li, Ying-Bo,Yan, Xu,Li, Ri-Dong,Liu, Peng,Sun, Shao-Qian,Wang, Xin,Cui, Jing-Rong,Zhou, De-Min,Ge, Ze-Mei,Li, Run-Tao
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p. 217 - 230
(2016/05/02)
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- SPIRO-OXADIAZOLINE COMPOUNDS AS AGONISTS OF α-7-NICOTINIC ACETYLCHOLINE RECEPTORS
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The present invention relates to novel spiro-oxadiazoline compounds that are suitable as agonists or partial agonists of a7-nAChR, and pharmaceutical compositions of the same, methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering a spiro-oxadiazoline cx7-nAChR agonist or partial agonist, to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
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Paragraph 00254-00255
(2015/05/19)
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- Synthesis and antimicrobial properties of 1,3,4-oxadiazole analogs containing dibenzosuberane moiety
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A series of ten novel 1,3,4-oxadiazole analogs containing dibenzosuberane moiety were synthesized using linear as well as convergent synthesis approach. All the compounds were characterized by mass spectrometry, infrared (IR), 1H and 13C nuclear magnetic resonance (1H NMR and 13C NMR) spectroscopies and elemental analysis. These compounds were evaluated for antibacterial and antifungal activities. Among ten analogs, four compounds, namely, 8a, 8d, 8e and 8j were found to be highly active antibacterial and antifungal agents.
- Moger, Manjunath,Satam, Vijay,Govindaraju, Darshan Raj C.,Paniraj,Gopinath, Vadiraj S.,Hindupur, Rama Mohan,Pati, Hari N.
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p. 104 - 111
(2014/02/14)
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- OXO-HETEROCYCLICALLY SUBSTITUTED ALKYL CARBOXYLIC ACIDS AND USE THEREOF
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The present application relates to novel alkylcarboxylic acids having an oxo-substituted azaheterocyclic partial structure, to processes for their preparation, to their use for the treatment and/or prevention of diseases, and to their use for producing medicaments for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
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Page/Page column 24
(2012/02/06)
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- Discovery of 2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile (Perampanel): A novel, noncompetitive α-amino-3-hydroxy-5- methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist
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Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate receptors. The structure-activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of 2-(2-oxo-1-phenyl-5- pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca2+ influx assay (IC50 = 60 nM) and in an in vivo AMPA-induced seizure model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy.
- Hibi, Shigeki,Ueno, Koshi,Nagato, Satoshi,Kawano, Koki,Ito, Koichi,Norimine, Yoshihiko,Takenaka, Osamu,Hanada, Takahisa,Yonaga, Masahiro
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p. 10584 - 10600
(2013/02/23)
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- OXO-HETEROCYCLIC SUBSTITUTED CARBOXYLIC ACID DERIVATIVES AND THE USE THEREOF
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The present application relates to novel carboxylic acid derivatives having an oxo-substituted azaheterocyclic partial structure, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
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Page/Page column 25
(2011/02/26)
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- Reaction of 3-formylchromone-N-benzoylhydrazone with ketenes. Synthesis and structural studies of chromone 1,3,4-oxadiazolines
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(Chemical Equation Presented) The reaction of 3-formylchromone-N- benzoylhydrazone with ketenes, prepared in situ from the corresponding acid chlorides 2a-d and the mixed anhydride 2e was studied. In all cases 2-(4′-oxo-4′H-3′-chromyl)-5-phenyl-2,3-dihydro-1,3, 4-oxadiazoles (3) were isolated in yields varying from 40 to 80%. A full structure assignment of all products has been made on the basis of 1D and 2-D (COSY H-H, COSY C-H, COLOC C-H) NMR spectra. A plausible reaction mechanism is also proposed based on theoretical approaches and experimental results.
- Kaspentakis, George C.,Tsoleridis, Constantinos A.,Stephanidou-Stephanatou, Julia
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p. 425 - 430
(2008/03/29)
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- Synthesis of [1,2,4]triazolo[4,3-α]piperazines via highly reactive chloromethyloxadiazoles
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(Chemical Equation Presented) A concise, modular approach for the synthesis of [1,2,4]triazolo[4,3-α]piperazines via condensation of highly reactive chloromethyloxadiazoles with ethylenediamines is described. NMR studies of this reaction provide evidence that suggests a novel activation mechanism for electron-deficient chloromethyloxadiazoles.
- Balsells, Jaume,DiMichele, Lisa,Liu, Jinchu,Kubryk, Michele,Hansen, Karl,Armstrong III, Joseph D.
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p. 1039 - 1042
(2007/10/03)
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- PROCESS TO TETRAHYDROTRIAZOLOPYRAZINES AND INTERMEDIATES
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A novel process is provided for the preparation of substituted-5,6,7,8-tetrahydro[1,2,4]-triazolo[4,3-alpha]pyrazines which are useful in the synthesis of dipeptidyl peptidase-IV inhibitors for the treatment of Type 2 diabetes. Also provided are useful intermediates obtained from the process.
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- Synthesis and antifeedant activity of new oxadiazolyl 3(2H)-pyridazinones
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A total of 20 new compounds containing the oxadiazolyl 3(2H)-pyridazinone moiety were synthesized. The structures of all the compounds were confirmed by 1H NMR, IR, MS, and elemental analysis. Their insect antifeedant activities against Asiatic corn borer Ostrinia furnacalis (Guenee) were examined and compared with commercial azadirachtin. The compounds exhibited significant levels of activity. The feeding deterrency values of IIIa,j were 57% and 51% at 500 mg/kg concentration, respectively.
- Cao, Song,Qian, Xuhong,Song, Gonghua,Chai, Bing,Jiang, Zhisheng
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p. 152 - 155
(2007/10/03)
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- Synthesis and insecticidal activity of neonicotinoids derivatives
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A new class of compounds- neonicotinoids containing oxadiazole -were synthesized and characterized by using 1H NMR, IR, MS and Elemental Analysis. Their insecticidal activities were tested against Mythimna separata Walker and Aphis rumicis Linnaeus, some of them showed some insecticidal activity.
- Chai, Bing,Cao, Song,Liu, Haidong,Song, Gonghua,Qian, Xuhong
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p. 601 - 606
(2007/10/03)
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