- Oxazole ring-containing honokiol thioether derivative and preparation method and application thereof
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The invention discloses an oxazole ring-containing honokiol thioether derivative, a preparation method thereof and application of the oxazole ring-containing honokiol thioether derivative as an alpha-glucosidase inhibitor, the chemical structure of the oxazole ring-containing honokiol thioether derivative is shown as a general formula (I), and R is selected from non-substituted or substituted phenyl. Compared with the prior art, the invention provides the novel honokiol thioether derivative containing the oxazole ring, and the honokiol thioether derivative containing the oxazole ring has good inhibitory activity on alpha-glucosidase, provides more possibilities for treating diabetes, and is expected to be used for preparing novel candidate drug molecules for treating diabetes. In addition, the preparation process is simple, the cost is low, and the yield is high.
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Paragraph 0042; 0047-0048
(2021/08/11)
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- Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies
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Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC50 0.041–0.081 μM, SI 139.74–321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3–48.3, 1 h; 58.4–60.5, 2 h; 70.8–83.2, 3 h; 78.9–89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.
- Alfayomy, Abdallah M.,Abdel-Aziz, Salah A.,Marzouk, Adel A.,Shaykoon, Montaser Sh. A.,Narumi, Atsushi,Konno, Hiroyuki,Abou-Seri, Sahar M.,Ragab, Fatma A.F.
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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 novel furo[2,3-d]pyrimidin-2-one–1,3,4-oxadiazole hybrid derivatives as dual antiviral and anticancer agents that induce apoptosis
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A new series of furo[2,3-d]pyrimidine–1,3,4-oxadiazole hybrid derivatives were synthesized via an environmentally friendly, multistep synthetic tool and a one-pot Songoashira-heterocyclization protocol using, for the first time, nanostructured palladium pyrophosphate (Na2PdP2O7) as a heterogeneous catalyst. Compounds 9a–c exhibited broad-spectrum activity with low micromolar EC50 values toward wild and mutant varicella-zoster virus (VZV) strains. Compound 9b was up to threefold more potent than the reference drug acyclovir against thymidine kinase-deficient VZV strains. Importantly, derivative 9b was not cytostatic at the maximum tested concentration (CC50 > 100 μM) and had an acceptable selectivity index value of up to 7.8. Moreover, all synthesized 1,3,4-oxadiazole hybrids were evaluated for their cytotoxic activity in four human cancer cell lines: fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A549). Data showed that compound 8f exhibits moderate cytotoxicity, with IC50 values ranging from 13.89 to 19.43 μM. Besides, compound 8f induced apoptosis through caspase 3/7 activation, cell death independently of the mitochondrial pathway, and cell cycle arrest in the S phase for HT1080 cells and the G1/M phase for A549 cells. Finally, the molecular docking study confirmed that the anticancer activity of the synthesized compounds is mediated by the activation of caspase 3.
- El Mansouri, Az-eddine,Oubella, Ali,Danoun, Karim,Ahmad, Mehdi,Neyts, Johan,Jochmans, Dirk,Snoeck, Robert,Andrei, Graciela,Morjani, Hamid,Zahouily, Mohamed,Lazrek, Hassan B.
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- Synthesis, biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents
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Twenty benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety were synthesized and evaluated for their anti-oxidant and anti-inflammatory activities. Among these compounds, 8h and 8l were appeared to have high radical scavenging efficacies as 0.05 ± 0.02 and 0.07 ± 0.03 mmol/L of IC50 values in ABTS+[rad] bioassay, respectively. In anti-inflammatory tests, compound 8h displayed good activity with 57.35% inhibition after intraperitoneal administration, which was more potent than the reference drug (indomethacin). Molecular modeling studies were performed to investigate the binding mode of the representative compound 8h into COX-2 enzyme. In vitro enzyme study implied that compound 8h exerted its anti-inflammatory activity through COX-2 inhibition.
- Bai, Xue-Qian,Cui, Ming-Yue,Li, Chun-Shi,Liang, Cheng-Wu,Song, Ze-Wen,Wang, Hui-Yan,Zhang, Tian-Yi,Zheng, Xian-Jing
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- Design, synthesis and biological evaluation of 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazole derivatives as anti-breast cancer agents
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Structural based molecular docking approach revealed the findings of 2-(phenoxymethyl) -5-phenyl-1,3,4-oxadiazole derivatives. The compounds (7a-o) were synthesized and characterized well by using conventional methods. The compounds, 7b and 7m were reconfirmed through single crystal XRD analysis. The synthesized compounds (7a-o) were evaluated their antiproliferative activities against MCF-7 and MDA-MB-453. Furthermore, Lipinski's rule of five and pharmacokinetic properties were predicted for the test compounds. These results demonstrate that the compounds 7b and 7d exhibit more potent cytotoxicity and 7d exhibits dose-dependent activity and reduced cell viability. Further, the mechanism of action for the induced apoptosis was observed through morphological changes and western blotting analysis. These findings may furnish the lead for further development.
- Lakshmithendral,Saravanan,Elancheran,Archana,Manikandan,Arjun,Ramanathan,Lokanath,Kabilan
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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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- Design, synthesis, and biological evaluation of novel dual FFA1 (GPR40)/PPARδ agonists as potential anti-diabetic agents
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The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) were considered as potential anti-diabetic targets, and the dual FFA1/PPARδ agonists might provide synergistic effect in insulin secretion and sensibility. Herein, we further develop dual agonists by screening 7 series of heterocycles, resulting in the discovery of compound 19 with considerable oral pharmacokinetic profile. Compound 19 exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound 19 exerted improved glucose-lowering effects and insulin sensitivity in a dose-dependent manner, which might be attributed to its dual effects to simultaneously regulate insulin secretion and resistance. Our results extended the existing chemical space, and provided a potent tool compound 19.
- Li, Zheng,Hu, Lijun,Wang, Xuekun,Zhou, Zongtao,Deng, Liming,Xu, Yawen,Zhang, Luyong
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- Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents
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Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100 mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50 >100 μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.
- Wei, Zhi-Yu,Chi, Ke-Qiang,Wang, Ke-Si,Wu, Jie,Liu, Li-Ping,Piao, Hu-Ri
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p. 1797 - 1803
(2018/04/23)
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- Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety
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A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC50 = 56 nM) and 9n against MOLT-4 (IC50 = 80 nM), more potent than monastrol (IC50 = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
- Ragab, Fatma A.F.,Abou-Seri, Sahar M.,Abdel-Aziz, Salah A.,Alfayomy, Abdallah M.,Aboelmagd, Mohamed
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p. 140 - 151
(2017/06/30)
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- Synthesis and electrochemical and antioxidant properties of chalcogenocyanate oxadiazole and 5-heteroarylchalcogenomethyl-1: H -tetrazole derivatives
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This article presents the chalcogenocyanate oxadiazoles 7 and 8 and their derivatives 5-heteroarylchalcogenomethyl-1H-tetrazoles 9 and 10, which were synthesized in high yields. The 5-substituted-1H-tetrazoles were obtained via [3+2] cycloaddition reactions of chalcogenocyanates 7 and 8 with sodium azide (NaN3) using a simple methodology. All the obtained compounds were characterized by NMR and high resolution mass spectrometry analysis. Their in vitro antioxidant activity was evaluated by measuring their ability to eliminate free radicals in the form of 2,2-diphenyl-2-picrylhydrazyl (DPPH) and through the reduction of molybdenum(vi) to molybdenum(v). The results for the phosphomolybdenum method indicated that some compounds have antioxidant properties, as evidenced by electrochemical oxidation tests to which they were subjected, which correlate their oxidation potentials (Epa) with their activity values (EC50).
- Leal, Julliano G.,Sauer, André C.,Mayer, Jo?o C. P.,Stefanello, Sílvio T.,Gon?alves, Débora F.,Soares, Felix A. A.,Iglesias, Bernardo A.,Back, Davi F.,Rodrigues, Oscar E. D.,Dornelles, Luciano
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supporting information
p. 5875 - 5883
(2017/07/10)
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- Conjugated oligo-aromatic compounds bearing a 3,4,5-trimethoxy moiety: Investigation of their antioxidant activity correlated with a DFT Study
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A series of heterocyclic compounds bearing the well-known free radical scavenging 3,4,5-trimethoxybenzyloxy group, was synthesized. The key compound 4-(3,4,5-trimethoxybenzyl-oxy)benzohydrazide was converted into thiosemicarbazide derivatives, which were
- Kareem, Huda S.,Nordin, Nurdiana,Heidelberg, Thorsten,Abdul-Aziz, Azlina,Ariffin, Azhar,Bunce, Richard A.
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- Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety
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A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC50 value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC50 values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC50 values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.
- Zhang, Kai,Wang, Peng,Xuan, Li-Na,Fu, Xiao-Yun,Jing, Fen,Li, Sha,Liu, Yu-Ming,Chen, Bao-Quan
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p. 5154 - 5156
(2014/12/11)
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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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- Synthesis and biological activity of 2-(bis((1,3,4-oxadiazolyl/1,3,4- thiadiazolyl)methylthio)methylene)malononitriles
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The reactivity of ketene dithiolates in the presence of different equivalents of sodium ethoxide was studied. 2-(Bis((5-aryl-1,3,4-oxadiazol-2-yl) methylthio)methylene)malononitriles 5 and 2-(bis((5-aryl-1,3,4-thiadiazol-2-yl) methylthio)methylene)malononitriles 6 were prepared by the reaction of malononitrile with carbon disulfide and 5-aryl-2-(chloromethyl)-1,3,4- oxadiazoles 3/5-aryl-2-(chloromethyl)-1,3,4-thiadiazoles 4. The preliminary antimicrobial and antioxidant activities of the lead compounds were assayed.
- Padmavathi,Dinneswara Reddy,Nagi Reddy,Mahesh
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experimental part
p. 1367 - 1373
(2011/04/24)
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- One-pot synthesis of 5-{[Bis(azolylmethylthio)]methylene}pyrimidine-2,4,6- (1H,3H,5H)-triones
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A new class of hitherto unknown trisheterocycles, bisoxadiazolyl/ bisthiadiazolyl pyrimidinetriones/thioxopyrimidinediones was prepared in a one-pot reaction and their antimicrobial activity was studied.
- Padmavathi, Venkatapuram,Reddy, Guda Dinneswara,Venkatesh, Bhumireddy Chinnachennaiahgari,Padmaja, Adivireddy
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body text
p. 165 - 169
(2011/10/05)
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- AZOLE DERIVATIVES AS WTN PATHWAY INHIBITORS
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The present invention relates to new compounds of formula I, to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy. Such compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the Wnt pathway. For example, these may be used in preventing and/or retarding proliferation of tumor cells, for example carcinomas such as colon carcinomas.
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Page/Page column 91-92; 102-103
(2010/12/29)
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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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