- Design, docking, synthesis, and characterization of novel N'(2-phenoxyacetyl) nicotinohydrazide and N'(2-phenoxyacetyl)isonicotinohydrazide derivatives as anti-inflammatory and analgesic agents
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Inflammation is the complex biological response of vascular tissues, which is partly determined by prostaglandins (PLA2). The cyclooxygenase (COX) enzyme exists in two isoforms: COX-1 and COX-2 and by the action of this, the PGs are produced. Besides, nonsteroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents useful in the treatment of inflammation. Encouraged by this, the new derivatives of N'(2-phenoxyacetyl)nicotinohydrazide 9(a-e) and N'(2-phenoxyacetyl)isonicotinohydrazide 10(a-e) were designed, synthesized, characterized, and identified as remarkable anti-inflammatory and analgesic agents. These compounds were prepared in a series of steps starting with different phenol derivatives. Among the series, compound (10e) showed the highest IC50 value for COX-1 inhibition, whereas compounds (9e) and (10e) exhibited the highest COX-2SI. Further, molecular Docking Studies have been performed for the potent compound to check the three-dimensional geometrical view of the ligand binding to the targeted enzymes.
- Al-Ostoot, Fares Hezam,Khanum, Shaukath Ara,M, Pallavi H,Vivek, Hamse Kameshwar
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- Design, synthesis and biological evaluation of oxime lacking Psammaplin inspired chemical libraries as anti-cancer agents
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In this study, we attempted the chemical simplification of Psammaplin (PsA), while retaining its activity in vitro. Inspired by the previous Structure Activity Relationship (SAR) studies on various PsA analogues and relying on the fact that oxime is metabolically unstable, we initially designed and synthesized a diverse library of PsA analogues and evaluated for cytotoxic activity. Among 32 compounds of Psammaplin analogues synthesized, the compound 10b was almost equally active as parent Psammaplin in vitro.
- Ali, Kasim,Chaturvedi, Priyank,Datta, Dipak,Kumar M, Srinivas Lavanya,Meena, Sanjeev,Panda, Gautam
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- Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs to induce anti-neoplasia
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Background: Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression. Methods: A new series of DPA (7a–t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches. Results: Initial in vitro anti-proliferative screening of Compounds DPA (7a–t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC50 value of 4.3?μM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways. Conclusions: Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity. Graphic abstract: [Figure not available: see fulltext.]
- Al-Ostoot, Fares Hezam,Sherapura, Ankith,Malojirao, Vikas H.,Thirusangu, Prabhu,Al-Muhimeed, Tahani I.,Khanum, Shaukath Ara,Prabhakar
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p. 1344 - 1360
(2021/06/14)
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- Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression
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Background: Hypoxic microenvironment is a common feature of solid tumors, which leads to the promotion of cancer. The transcription factor, HIF-1α, expressed under hypoxic conditions stimulates tumor angiogenesis, favoring HIF-1α as a promising anticancer agent. On the other hand, synthetic Indolephenoxyacetamide derivatives are known for their pharmacological potentiality. With this background here, we have synthesized, characterized, and validated the new IPA (8a–n) analogs for anti-tumor activity. Methods: The new series of IPA (8a–n) were synthesized through a multi-step reaction sequence and characterized based on the different spectroscopic analysis FT-IR, 1H, 13C NMR, mass spectra, and elemental analyses. Cell-based screening of IPA (8a–n) was assessed by MTT assay. Anti-angiogenic efficacy of IPA (8k) validated through CAM, Rat corneal, tube formation and migration assay. The underlying molecular mechanism is validated through zymogram and IB studies. The in vivo anti-tumor activity was measured in the DLA solid tumor model. Results: Screening for anti-proliferative studies inferred, IPA (8k) is a lead molecule with an IC50 value of ?5?μM. Anti-angiogenic assays revealed the angiopreventive activity through inhibition of HIF-1α and modulation downstream regulatory genes, VEGF, MMPs, and P53. The results are confirmative in an in vivo solid tumor model. Conclusion: The IPA (8k) is a potent anti-proliferative molecule with anti-angiogenic activity and specifically targets HIF1α, thereby modulates its downstream regulatory genes both in vitro and in vivo. The study provides scope for new target-specific drug development against HIF-1α for the treatment of solid tumors. Graphic abstract: [Figure not available: see fulltext.].
- Al-Ostoot, Fares Hezam,Sherapura, Ankith,V, Vigneshwaran,Basappa, Giridhara,H.K, Vivek,B.T, Prabhakar,Khanum, Shaukath Ara
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p. 1328 - 1343
(2021/05/03)
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- Discovery, synthesis and biological characterization of a series of: N -(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1 H -pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators
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The present study describes the discovery and characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as G protein-gated inwardly-rectifying potassium (GIRK) channel activators. From our previous lead optimization efforts, we have identified a new ether-based scaffold and paired this with a novel sulfone-based head group to identify a potent and selective GIRK1/2 activator. In addition, we evaluated the compounds in tier 1 DMPK assays and have identified compounds that display nanomolar potency as GIRK1/2 activators with improved metabolic stability over the prototypical urea-based compounds. This journal is
- Alnouti, Yazen,Aretz, Christopher D.,Chhonker, Yashpal S.,Dhuria, Nikilesh V.,Du, Yu,Gautam, Nagsen,Hopkins, Corey R.,Kumar, Sushil,Lesiak, Lauren,Sharma, Swagat,Weaver, C. David
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supporting information
p. 1366 - 1373
(2021/09/28)
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- NOVEL COMPOUNDS AND THERAPEUTICS USES THEREOF
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The invention relates to novel compounds with the ability to link an immune response to a defined therapeutic target, to the use of said compounds in treating cancer and infectious diseases, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.
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Paragraph 0457-0460
(2020/08/05)
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- ROLES OF MODULATORS OF INTERSECTIN-CDC42 SIGNALING IN ALZHEIMER'S DISEASE
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Methods of treating Alzheimer's disease and other neurodegenerative and/or neurocognitive and/or neurodevelopmental diseases are described. The methods comprise the administration of compounds that modulate an activity of cell division control protein 42 (Cdc42), such as the interaction between Cdc42 and intersectin (ITSN). Exemplary modulator compounds include thioureas, disulfonamides of fused aromatic systems (e.g., benzofuran), and acyl hydrazones, among others. Some of the modulator compounds act as activators of Cdc42, while others act as inhibitors. In some cases, the modulator compound has dual functionality and the ability of the modulator compound to act as an inhibitor or activator depends on whether or not Cdc42 is already activated in a particular disease stage or biological environment by an upstream activating signal of Cdc42.
- -
-
Paragraph 0272; 0275
(2019/04/14)
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- Method for synthesizing p-bromophenoxyacetic acid
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The invention discloses a method for synthesizing p-bromophenoxyacetic acid. The method prepares p-bromophenoxyacetic acid through continuous reactions via a Corning G1 microchannel reactor and comprises the following steps: pumping an aqueous sodium bromide solution and an aqueous sodium hypochlorite solution in a certain ration into a first-stage reactor to prepare a high-activity bromination agent, i.e., bromine chloride; and pumping an ethanol solution of phenoxyacetic acid and bromine chloride produced in the first-stage reactor into a second-stage reactor so as to realize high-efficiencyand high-selectivity preparation of p-bromophenoxyacetic acid, wherein yield is as high as 94.3%.
- -
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Paragraph 0019-0026
(2019/03/15)
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- Novel pyrazolone derivatives and corresponding europium(III) complexes: Synthesis and properties research
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A series of pyrazolone derivatives ligands L1?7 were successfully synthesized and validated by 1H NMR and MS, corresponding europium complexes [EuL1?7(NO3)2]NO3·EtOAc were synthesized. Physico-chemistry properties of title complexes were determined by Elemental analysis, Molar conductance, UV absorption spectra, IR spectra and Thermogravimetric analysis. The title complexes exhibit characteristic red fluorescence of Eu3+. The effect of various substituent groups in ligands on the of title Eu3+ complexes is ordered: Cl > -Br > -OCH3 > -F > -CH3 > -H > -NO2, and [EuL6(NO3)2]NO3·EtOAc containing Cl possesses the strongest fluorescence intensity, so does fluorescence quantum yield. The electrochemical properties indicate that energy gap Eg and LUMO energy level are huge affected by substituent groups, and variation trends of LUMO energy level affected by diverse substituent groups are also different. The prepared title europium complexes have potential application prospects in the fields of photoelectric functional materials and life sciences.
- Li, Dewei,Xiong, Suhao,Guo, Tiantong,Shu, Dehua,Xiao, Haihua,Li, Guizhi,Guo, Dongcai
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- Synthesis and luminescence properties of novel 8-hydroxyquinoline derivatives and their Eu(III) complexes
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Six novel 8-hydroxyquinoline derivatives were synthesized using 2-methyl-8-hydroxyquinoline and para-substituted phenol as the main starting materials, and were characterized by 1H nuclear magnetic resonance (NMR), mass spectrometry (MS), ultraviolet (UV) light analysis and infra-red (IR) light analysis. Their complexes with Eu(III) were also prepared and characterized by elemental analysis, molar conductivity, UV light analysis, IR light analysis, and thermogravimetric–differential thermal analysis (TG–DTA). The results showed that the ligand coordinated well with Eu(III) ions and had excellent thermal stability. The structure of the target complex was EuY1–6(NO3)3.2H2O. The luminescence properties of the target complexes were investigated, the results indicated that all target complexes had favorable luminescence properties and that the introduction of an electron-donating group could enhance the luminescence intensity of the corresponding complexes, but the addition of an electron-withdrawing group had the opposite effect. Among all the target complexes, the methoxy-substituted complex (–OCH3) had the highest fluorescence intensity and the nitro-substituted complex (–NO2) had the weakest fluorescence intensity. The results showed that 8-hydroxyquinoline derivatives had good energy transfer efficiency for the Eu(III) ion. All the target complexes had a relatively high fluorescence quantum yield. The fluorescence quantum yield of the complex EuY3(NO3)3.2H2O was highest among all target complexes and was up to 0.628. Because of excellent luminescence properties and thermal stabilities of the Eu(III) complexes, they could be used as promising candidate luminescent materials.
- Wu, Yongqiang,Guo, Tiantong,Shu, Dehua,Zhang, Wu,Luan, Fangfei,Shi, Ling,Guo, Dongcai
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p. 855 - 862
(2018/07/13)
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- Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents
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A series of new aryloxyacetamide derivatives 10a-s and 14a-m are designed and synthesized. Their protective activities against the glutamate-induced cell death were investigated in differentiated rat pheochromocytoma cells (PC12 cells). Most compounds exhibited neuroprotective effects, especially for 10m, 10r, 14b and 14c, which showed potential protection of PC12 cells at three doses (0.1, 1.0, 10 μM). MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 10m, 10r, 14b and 14c has significantly decreased the extent of cell apoptosis in a dose-dependent manner. The results of western blot analysis demonstrated these compounds suppressed apoptosis of glutamate-induced PC12 cells via caspase-3 pathway. These compounds can be lead compounds for further discovery of neuroprotective agents for treating cerebral ischemic stroke. Basic structure-activity relationships are also presented.
- Zhong, Yan,Xu, Yi,Zhang, Ai-Xia,Li, Xiao-Feng,Xu, Zhao-Ying,Li, Ping,Wu, Bin
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supporting information
p. 2526 - 2530
(2016/07/07)
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- Synthesis and properties of coumarin derivatives and their terbium complexes
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A series of coumarin derivatives obtained from salicylaldehyde and phenol were synthesized. Their corresponding terbium complexes were prepared and characterized by elemental analysis, EDTA titrations, molar conductivity, UVvis spectra, IR spectra, and thermal analysis. The luminescent properties and electrochemical properties of the terbium complexes were also investigated. The results showed that all the terbium complexes exhibited characteristic emissions of terbium ions. The introduction of electron-donating groups can improve the luminescent properties, decrease the HOMO and LUMO energy levels of the terbium complex, while electron-withdrawing groups can weaken the luminescent properties, and increase the HOMO and LUMO energy levels of terbium complex.
- Meng, Defen,Xu, De,Li, Dong,Dai, Ming,Li, Guizhi,Guo, Dongcai
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p. 5269 - 5280
(2016/06/01)
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- Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1and A2Areceptor antagonists
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Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A1adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A1and A2Aadenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A1and A2Aadenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A1and A2Abinding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A1affinity except for the 4-Br analog (4f) exhibiting the best A1affinity in the submicromolar range. On the other hand A2Aaffinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH3(4b) analog showed the best A2Aaffinity with a Kivalue of 237?nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A1adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A1adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A1and A2Aadenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease.
- Harmse, Rozanne,van der Walt, Mietha M.,Petzer, Jacobus P.,Terre'Blanche, Gisella
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supporting information
p. 5951 - 5955
(2016/12/03)
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- Radical decarboxylative fluorination of aryloxyacetic acids using N-fluorobenzenesulfonimide and a photosensitizer
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Fluorinated methoxy arenes are emerging as important motifs in both agrochemicals and pharmaceuticals. A novel technique for the synthesis of monofluoromethoxy arenes through the direct fluorodecarboxylation of carboxylic acids was developed that uses photosensitizers and N-fluorobenzenesulfonimide (NFSI). Utilization of the oxidatively mild fluorine transfer agent NFSI enabled the synthesis of fluoromethyl ethers that were previously inaccessible with decarboxylative fluorinations performed with Selectfluor. Mechanistic studies are consistent with the photosensitizer effecting oxidation of the aryloxyacetic acid.
- Leung, Joe C. T.,Sammis, Glenn M.
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supporting information
p. 2197 - 2204
(2015/04/14)
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- Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera
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Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white-backed planthopper Sogatella furcifera.
- He, Xingrui,Yu, Zhaonan,Jiang, Shaojie,Zhang, Peizhi,Shang, Zhicai,Lou, Yonggen,Wu, Jun
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supporting information
p. 5601 - 5603
(2015/11/17)
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- Synthesis, Characterization and Properties of Novel Coumarin Derivatives and Their Europium Complexes
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Seven novel coumarin derivatives derived from salicylaldehyde and phenol were synthesized and characterized by 1H NMR and 13C NMR spectra, mass spectra, infrared spectra and elemental analysis. Their corresponding Eu(III) complexes having general formula EuL1-7(NO3)3·2H2O were successfully prepared and characterized by elemental analysis, EDTA titrimetric, molar conductivity, UV-Vis, FT-IR and thermal performance studies. The luminescence properties, fluorescence quantum yields and the electrochemical properties of the title complexes were investigated. The results showed that the title complexes exhibited characteristic emissions of europium ions and possessed relatively good fluorescence quantum yields. The luminescence intensity of the complex with bromine-substituted group is the strongest among all the title complexes. The introduction of electron-withdrawing groups can increase the luminescence properties and fluorescence quantum yields, decrease the HOMO and LUMO energy levels of the title europium complexes, but electron-withdrawing group conversely. And these title complexes may possibly be useful for studying in luminescent materials field.
- Yan, Dong,Li, Dong,Cheng, Guang,Yang, Zehui,Shi, Ling,Guo, Dongcai
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p. 849 - 859
(2015/08/24)
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- Synthesis and luminescence properties of pyrazolone derivatives and their terbium complexes
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Seven novel pyrazolone derivatives were synthesized and characterized by 1H NMR and 13C NMR spectra, mass spectra, infrared spectra and elemental analysis. Their terbium complexes were prepared and characterized by elemental analysis, EDTA titrimetric analysis, UV/vis spectra, infrared spectra and molar conductivity, as well as thermal analysis. The fluorescence properties and fluorescence quantum yields of the complexes were investigated at room temperature. The results indicated that pyrazolone derivatives had good energy-transfer efficiency for the terbium ion. All the terbium complexes emitted green fluorescence characteristic of terbium ions, possessed strong fluorescence intensity, and showed relatively high fluorescence quantum yields. Cyclic voltammograms of the terbium complexes were studied and the highest occupied molecular orbital (HOMO) and lowest occupied molecular orbital (LUMO) energy levels of these complexes were estimated.
- Xiao, Haihua,Jiang, Xi,Li, Dong,Wu, Limin,Zhang, Wu,Guo, Dongcai
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p. 677 - 685
(2015/12/04)
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- Synthesis, evaluation and in silico molecular modeling of pyrroyl-1,3,4-thiadiazole inhibitors of InhA
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Enoyl acyl carrier protein reductase (ENR) is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents. Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA). Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4-thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods.
- Joshi, Shrinivas D.,More, Uttam A.,Koli, Deepshikha,Kulkarni, Manoj S.,Nadagouda, Mallikarjuna N.,Aminabhavi, Tejraj M.
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p. 151 - 167
(2015/03/30)
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- Synthesis and fluorescence properties of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol derivatives and their terbium complexes
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Eight novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol derivatives have been designed and synthesized, and their corresponding Tb3+ complexes were also prepared successfully. The fluorescence properties and fluorescence quantum yields of the target complexes were investigated, the results showed that the ligands were an efficient sensitizer for Tb3+ luminescence, and the target complexes exhibited characteristic fluorescence emissions of Tb3+ ion. The fluorescence intensity of the complex substituted by chlorine was stronger than that of other complexes. The substituents' nature has a great effect upon the electrochemical properties of the target complexes. The results showed that the introduction of the electron-withdrawing groups tended to decrease the oxidation potential and highest occupied molecular orbital energy levels of the target Tb3+ complexes; however, introduction of the electron-donating groups can increase the corresponding complexes' oxidation potential and highest occupied molecular orbital energy levels.
- Zhang, Wu,Chai, Yuchao,Li, Kangyun,Chen, Yanwen,Yan, Dong,Guo, Dongcai
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p. 1113 - 1122
(2015/02/19)
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- METALLOENZYME INHIBITOR COMPOUNDS
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The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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-
Page/Page column 141-142
(2014/08/07)
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- In silico and pharmacological screenings identify novel serine racemase inhibitors
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d-Serine is a coagonist of the N-methyl-d-aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by serine racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50 value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.
- Mori, Hisashi,Wada, Ryogo,Li, Jie,Ishimoto, Tetsuya,Mizuguchi, Mineyuki,Obita, Takayuki,Gouda, Hiroaki,Hirono, Shuichi,Toyooka, Naoki
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p. 3732 - 3735
(2014/09/03)
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- Synthesis, characterization and properties of 1,2,4-triazolo[3,4-b][1,3,4] thiadiazole derivatives and their europium complexes
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Eight novel 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives and their corresponding Eu(III) complexes were synthesized and characterized. From the spectral studies it has been concluded that the title Eu(III) complexes display six coordination. The investigation of the luminescence properties of the title complexes showed that the ligands favor energy transfers to the emitting energy level of europium ions. The title Eu(III) complexes exhibited characteristic emissions of europium ions, and possessed strong luminescence intensities, good fluorescence quantum yields, and the highest fluorescence quantum yield is up to 0.522. Furthermore, the luminescence intensity of the complex with chlorine-substituted group is the strongest than that of other complexes. The exploration of the electrochemical properties of the title complexes shows that the introduction of electron-donating groups can increase the HOMO energy levels, LUMO energy levels and the oxidation potential of the complexes, however, the result of introduction of electron-withdrawing groups was just opposite.
- Yan, Dong,Xiang, Yu,Li, Kangyun,Chen, Yanwen,Yang, Zehui,Guo, Dongcai
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p. 487 - 495
(2014/07/21)
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- Design, synthesis, molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as potential antimycobacterial agents
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In order to develop a lead antimycobacterium tuberculosis compound, a series of 52, novel pyrrole hydrazine derivatives have been synthesized and screened which target the essential enoyl-ACP reductase. The binding mode of the compounds at the active site of enoyl-ACP reductase was explored using surflex-docking method. The binding model suggests one or two hydrogen bonding interactions between pyrrole hydrazones and InhA enzyme. Highly active compound 5r (MIC 0.2 μg/mL) showed hydrogen bonding interactions with Tyr158 and NAD+ in the same manner as those of ligands PT70 and triclosan. The CoMFA and CoMSIA models generated with database alignment were the best in terms of overall statistics. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (rpred2) of 0.896 and 0.930, respectively.
- More, Uttam A.,Joshi, Shrinivas D.,Aminabhavi, Tejraj M.,Gadad, Andanappa K.,Nadagouda, Mallikarjuna N.,Kulkarni, Venkatrao H.
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p. 199 - 218
(2014/01/06)
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- Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors
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By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO2 in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.
- He, Jun-Bo,Ren, Yan-Liang,Sun, Qiu-Shuang,You, Ge-Yun,Zhang, Li,Zou, Peng,Feng, Ling-Ling,Wan, Jian,He, Hong-Wu
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p. 3180 - 3186
(2014/06/09)
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- Development of hypoxia-inducible factor (HIF)-1α inhibitors: Effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia
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A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI50) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC50: 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC50: 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC50: 10.9 ± 0.63 μM).
- Nakamura, Hiroyuki,Yasui, Yuka,Maruyama, Minako,Minegishi, Hidemitsu,Ban, Hyun Seung,Sato, Shinichi
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p. 806 - 810
(2013/02/25)
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- Synthesis and antimicrobial activity of phthalazines and pyridazines
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A new series of 2,3-dihydro phthalazine-1,4-diones, Va-b and 2,3,4,5-tetrahydro pyridazine-3,6-diones Vla-b were synthesized using p-chloro phenol and p-bromo phenol, as starting materials. The final compounds were prepared by reacting corresponding hydrazides with phthalic anhydride and succinic anhydride to get Va-b, Vla-b by fusion reaction. Structures of the synthesized compounds were confirmed on the basis of physical and spectral data (IR, 1H NMR and Mass). All the synthesized compounds were screened for their antimicrobial activity. Minimum inhibitory cone for the synthesized compounds were determined by using broth micro dil method. Among the synthesized compounds, compound Vb, having bromine at para position of the aromatic ring was found to be active at the lowest cone of 0.005 μM/ml against Gram positive bacteria Bacillus subtilis as compared to standard Ciprofloxacin, Norfloxacin and compound Vb was found active at the concentration of 0.005 μM/ml against fungi Candida albicans as compared to standard Fluconazole and Griseofulvin.
- Purohit, Shriram S.,Patil, Pavan A.
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p. 269 - 272
(2013/09/24)
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- A specific protein disorder catalyzer of HIV-1 Nef
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The HIV-1 auxiliary protein Nef is required for the onset and progression of AIDS in HIV-1-infected persons. Here, we have deciphered the mode of action of a second-generation inhibitor of Nef, DLC27-14, presenting a competitive IC50 of ~16 μM measured by MALDI-TOF experiments. Thermal protein denaturation experiments revealed a negative effect on stability of Nef in the presence of a saturating concentration of the inhibitor. The destabilizing action of DLC27-14 was confirmed by a HIV protease-based experiment, in which the protease sensitivity of DLC27-14-bound Nef was three times as high as that of apo Nef. The only compatible docking modes of action for DLC27-14 suggest that DLC27-14 promotes an opening of two α-helices that would destabilize the Nef core domain. DLC27-14 thus acts as a specific protein disorder catalyzer that destabilizes the folded conformation of the protein. Our results open novel avenues toward the development of next-generation Nef inhibitors.
- Lugari, Adrien,Breuer, Sebastian,Coursindel, Thibault,Opi, Sandrine,Restouin, Audrey,Shi, Xiaoli,Nazabal, Alexis,Torbett, Bruce E.,Martinez, Jean,Collette, Yves,Parrot, Isabelle,Arold, Stefan T.,Morelli, Xavier
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supporting information; experimental part
p. 7401 - 7406
(2012/02/02)
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- Studies of O,O-Dimethyl α-(2,4-Dichlorophenoxyacetoxy) ethylphosphonate (HW02) as a new herbicide. 1. Synthesis and herbicidal activity of HW02 and analogues as novel inhibitors of pyruvate dehydrogenase complex
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On the basis of the previous work for optimization of O,O-diethyl α-(substituted phenoxyacetoxy)alkylphosphonates, further extensive syntheticmodifications were made to the substituents in alkylphosphonate and phenoxymoieties of the title compounds. New O,O-dimethyl α-(substituted phenoxyacetoxy)alkylphosphonates were synthesized as potential inhibitors of pyruvate dehydorogenase complex (PDHc). Their herbicidal activity and efficacy in vitro against PDHc were examined. Some of these compounds exhibited significant herbicidal activity and were demonstrated to be effective inhibitors of PDHc from three different plants. The structure-activity relationships of these compounds including previously reported analogous compoundswere studied by examining their herbicidal activities. Both inhibitory potency against PDHc and herbicidal activity of title compounds could be increased greatly by optimizing substituent groups of the title compounds. O,O-Dimethyl α-(2,4- dichlorophenoxyacetoxy)ethylphosphonate (I-5), which acted as a competitive inhibitor of PDHc with much higher inhibitory potency against PDHc from Pisum sativum and Phaseolus radiatus than from Oryza sativa, was found to be themost effective compound against broadleaf weeds and showed potential utility as herbicide.
- He, Hong-Wu,Yuan, Jun-Lin,Peng, Hao,Chen, Ting,Shen, Ping,Wan, Shu-Qing,Lee, Yanjun,Tan, Hong-Liang,He, Ya-Hui,He, Jun-Bo,Li, Yan
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scheme or table
p. 4801 - 4813
(2011/12/04)
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- NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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[1,2,4]Triazolo[1,5-a]pyridine compounds are disclosed that have a formula represented by the following: (I) These compound may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) and proliferative diseases.
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Page/Page column 76
(2010/04/03)
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- Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid derivatives
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A series of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid (norfloxacin) derivatives were prepared according to the principle of combinating bioactive substructures and tested for their activities against five plant pathogenic bacteria and three fungi in vitro. The preliminary bioassays indicated that almost all synthesized target compounds retained the antibacterial activities of norfloxacin and had some antifungal activities as carboxylic acid amide compounds. The activities of compounds 1 and 22 against Xanthomonas oryzae were better than norfloxacin and all tested compounds had better antibacterial activities as compared to the agricultural streptomycin sulfate (a commercial bactericide) against X. oryzae, Xanthomonas axonopodis and Erwinia aroideae. Additionally, compounds 2 and 20 displayed good antifungal activities against Rhizoctonia solani and their inhibition of growth reached 83% and 94% respectively at the concentration of 200 mg/L.
- Yu, Zhiyi,Shi, Guanying,Sun, Qiu,Jin, Hong,Teng, Yun,Tao, Ke,Zhou, Guoping,Liu, Wei,Wen, Fang,Hou, Taiping
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scheme or table
p. 4726 - 4733
(2010/01/06)
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- Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines
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A series of potential biologically active 2-aryloxy methyl oxazolines 3a-n have been synthesized from substituted hydroxybenzenes 1a-n with good chemical yield. The compounds 3a-n were screened for their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone. The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-inflammatory activity with low ulcerogenic activity than the standard drugs.
- Khanum, Shaukath Ara,Khanum, Noor Fatima,Shashikanth
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body text
p. 4597 - 4601
(2009/04/06)
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- (Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors
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Structural modification of a compound discovered during screening using an HRE-dependent reporter assay has revealed a novel class of HIF-1 inhibitors, which potently inhibit the HIF-1α protein accumulation and its target gene expression under hypoxic conditions in human hepatocellular carcinoma Hep3B cells.
- Lee, Kyeong,Lee, Jeong Hyung,Boovanahalli, Shanthaveerappa K.,Jin, Yinglan,Lee, Mijeoung,Jin, Xuejun,Kim, Jin Hwan,Hong, Young-Soo,Lee, Jung Joon
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p. 1675 - 1684
(2008/02/01)
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- THIOPYRAN COMPOUNDS AS INHIBITORS OF MMP
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A compound of formula (I) in which R is lower alkyl, halogen, optionally substituted heterocyclic group or optionally substituted aryl, R is carboxy, protected carboxy or amidated carboxy, Ar is optionally substituted aryl or optionally substituted heterocyclic group, A is lower alkylene, X is oxa or a single bond, Y is thia, sulfinyl or sulfonyl, Z is methylene, thia, sulfinyl or sulfonyl, m and n are each an integer of 0 to 6, and 1/=m+n/=6, or its salt, which is useful as an inhibitor of matrix metalloproteinases (MMP) or tumor necrosis factor alpha (TNF alpha ).
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- Facile Hydrolysis of Esters with KOH-Methanol at Ambient Temperature
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A simple, rapid, and efficient method is reported for the hydrolysis of a variety of mono-and diesters of aromatic, aliphatic, fatty, and heterocyclic acids with potassium hydroxide in methanol at ambient temperature (~35°C).
- Khurana, Jitender M.,Chauhan, Sushma,Bansal, Geeti
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- Synthesis of Aryloxyacetic Acids, Esters, and Hydrazides Assisted by Microwave Irradiation
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Under microwave irradiation on clay a series of transformations of a number of phenols into their aryloxyacetic acids 3 and then their methyl esters 4 and hydrazides 5 has been achieved efficiently in good yields.
- Hamid, Hamida M. Abdel,Ramadan, El Sayed,Hagar, Mohamed,El Ashry, El Sayed H.
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p. 377 - 382
(2007/10/03)
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- Kinetics and mechanism of thermal gas-phase elimination of 2-aryloxyacetic acid
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Rates of thermal gas-phase elimination of eleven 2-aryloxyacetic acid have been measured over a 45°C temperature range for each compound. Hammett correlation of the present kinetic data with the literature σ0 values of the given substituents gave a reaction ρ constant of 0.69 at 600 K; this is more than that for the gas-phase elimination parameter of 2-aryloxypropanoic acid (ρ = 0.26) and consistent with a transition state with some charge separation, suggesting a partial formation of carbocation. The implications of this observation for the thermal gas-phase elimination of α-aryloxycarboxylic acids are considered.
- Al-Awadi, Nouria A.,Kumar, Ajith,Chuchani, Gabriel,Herize, Armando
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p. 612 - 616
(2007/10/03)
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- Fused piperidine substituted arylsulfonamides as beta 3-agonists
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Fused piperidine substituted arylsulfonamides are beta 3 adrenergic receptor agonists with very little beta 1 and beta 2 adrenergic receptor activity and as such the compounds are capable of increasing lipolysis and energy expenditure in cells. The compounds thus have potent activity in the treatment of Type II diabetes and obesity. The compounds can also be used to lower triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to decrease gut motility. In addition, the compounds can be used to reduced neurogenic inflammation or as antidepressant agents. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for decreasing gut motility are also disclosed.
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- benzenes
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The title compounds (3) have been prepared and their chemical properties studied.With iodine they give aryloxymethyl aryloxyacetates (4) through the intermediacy of aryloxyacetyl hypoiodites and α-iodoanisoles.The former are unstable but have been trapped with pyridine to give N-iodopyridinium aryloxyacetates, whereas the latter are stable and react independently with compounds (3) to afford the acetates (4).The termolysis of (3) has been studied and, besides esters (4), aryl aryloxyacetates are also formed.The mechanism of the thermolysis is briefly discussed.
- Menkisoglou-Spyroudi, Ourania,Varvoglis, Anastasios
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p. 795 - 798
(2007/10/02)
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- Design, Synthesis, and Testing of Potential Antisickling Agents. 4. Structure-Activity Relationships of Benzyloxy and Phenoxy Acids
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In this paper we further establish the activity of two classes of small molecules, benzyloxy and phenoxy acids, as potent inhibitors of hemoglobin S (HbS) gelation.Structural modifications with a large number of each class confirm our earlier work that the highest activity is observed with compounds that contain dihalogenated aromatic rings with attached polar side chains.We have also found a halogenated aromatic malonic acid derivative to be quite active.Compounds reported in this paper are compared with other antigelling agents studied in our laboratory.Comments are made concerning the antigelling activity and binding sites of four derivatives and their effect on the allosteric mechanism of hemoglobin (Hb) function.
- Abraham, D. J.,Kennedy, P. E.,Mehanna, A. S.,Patwa, D. C.,Williams, F. L.
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p. 967 - 978
(2007/10/02)
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- Applicability of Hammett Equation to Insulated Systems - Kinetics of Alkaline Hydrolysis of meta- and para-Substituted Methyl Phenoxyacatates
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The kinetics of alkaline hydrolysis of some meta- and para-substituted methyl phenoxyacetates have been determined in 85percent (wt/wt) methanol-water at 10 deg C, 15 deg C, and 20 deg C.The activation parameters have been evaluated from Arrhenius plots and the isokinetic temperature has been analysed.The applicability of Hammett equation to the above reaction has been discussed.The interesting behaviour of halogeno substituents is also discussed.
- Gurumurthy, R.,Balakrishnan, N.
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p. 154 - 156
(2007/10/02)
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- The Synthesis of Spirodioxetanes>
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It is shown that the spiroadamantane group stabilizes thermally labile 1,2-dioxetanes sufficiently to permit isolation.With the help of this stabilizing group it was possible to prepare the first sulfur substituted dioxetanes 9k and l and characterize them by low temperature 13C and 1H NMR spectra.Photosensitized singlet oxygenation at low temperature, using either polymer-bound Rose-Bengal or tetraphenylporphyrin as sensitizer in methylene chloride, of the corresponding 2-methyleneadamantanes 8 was the method of choice for the preparation of the spirodioxetanes> 9, provided that the methylene carbon bears no alkyl or phenyl substituents.The Kopecky method, i. e. hydroperoxybromination of the 2-methyleneadamantanes 8 and subsequent dehydrobromination, proved unsuccessful to prepare the dioxetanes 9.
- Adam, Waldemar,Encarnacion, Luis A. Arias
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p. 2592 - 2605
(2007/10/02)
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