- Synthesis and Biological Activity of 4-[(Substituted Phenoxyacetoxy)methyl]-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-one
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A series of novel 4-[(substituted phenoxyacetoxy)methyl]-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-one 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n, 4o were synthesized. Their structures were confirmed by IR,1H NMR, mass spectroscopy, and elemental analyses. The results of preliminary bioassays show that some of the title compounds exhibit moderate to good herbicidal and fungicidal activities. For example, the title compounds 4b, 4c, 4f, 4h, 4i, and 4j possess 90–100% inhibition against the growth of roots of both rape and barnyard grass at 10 mg/L. Moreover, the title compounds 4f, 4g, and 4h possess 75–89% inhibition against Botrytis cinerea at the concentration of 50 mg/L.
- Sheng, Xijun,Zhou, Yuan,Zhang, Shasha,Peng, Hao,He, Hongwu
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p. 165 - 170
(2017/02/03)
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- Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-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) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice.
- Li, Zheng,Wang, Xuekun,Xu, Xue,Yang, Jianyong,Qiu, Qianqian,Qiang, Hao,Huang, Wenlong,Qian, Hai
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supporting information
p. 6666 - 6672
(2015/10/19)
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- Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors
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Screening of the 50 000 ChemBridge compound library led to the identification of the oxadiazole-isopropylamide 1 (PI-1833) which inhibited chymotrypsin-like (CT-L) activity (IC50 = 0.60 μM) with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L). LC-MS/MS and dialysis show that 1 is a noncovalent and rapidly reversible CT-L inhibitor. Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 = 27 nM). Detailed SAR studies indicate that the amide moiety and the two phenyl rings are sensitive toward modifications. Hydrophobic residues, such as propyl or butyl in the para position (not ortho or meta) of the A-ring and a m-pyridyl group as B-ring, significantly improve activity. Compound 11ad (IC50 = 0.37 μM) is more potent than 1 (IC50 = 3.5 μM) at inhibiting CT-L activity in intact MDA-MB-468 human breast cancer cells and inhibiting their survival. The activity of 11ad warrants further preclinical investigation of this class as noncovalent proteasome inhibitors.
- Ozcan, Sevil,Kazi, Aslamuzzaman,Marsilio, Frank,Fang, Bin,Guida, Wayne C.,Koomen, John,Lawrence, Harshani R.,Sebti, Sa?d M.
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p. 3783 - 3805
(2013/06/27)
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- PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS
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Focused library synthesis and medicinal chemistry on an oxadiazole- isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring?s para-position and meta-pyridyl group at the B- ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer)
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Page/Page column 67
(2012/10/08)
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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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experimental part
p. 4726 - 4733
(2010/01/06)
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- Fluorescence switch-on sensor for Cu2+ by an amide linked lower rim 1,3-bis(2-picolyl)amine derivative of calix[4]arene in aqueous methanol
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A highly selective fluorescence switch on sensor, L for detecting Cu2+ has been synthesized by introducing a bis-(2-picolyl)amine moiety at the lower rim of a calix[4]arene platform via amide linkage. Binding properties of L toward ten different biologically relevant Mn+ ions have been studied by fluorescence and absorption spectroscopy in methanol and aqueous methanol. L was found to detect Cu2+ selectively down to a concentration of 196 and 341 ppb, respectively, in methanol and 1:1 aqueous methanol even in the presence of other metal ions. The composition of the complex has been found to be 1:1 based on the Job plot and is further confirmed by ESI MS. The role of calix[4]arene platform as well as the pre-organized binding core in the selective recognition of Cu2+ has been demonstrated by studying appropriate reference molecules. The possible modes of binding of L with Cu2+ have been modeled by computational calculations. L and its Cu2+ complex could very well be differentiated based on the nano-structural features observed in SEM and AFM.
- Joseph, Roymon,Ramanujam, Balaji,Acharya, Amitabha,Rao, Chebrolu P.
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scheme or table
p. 2735 - 2739
(2009/09/06)
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- Lower rim 1,3-di{bis(2-picolyl)}amide derivative of calix[4]arene (L) as ratiometric primary sensor toward Ag+ and the complex of Ag + as secondary sensor toward cys: Experimental, computational, and microscopy studies and INHIBIT logic gate properties of L
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(Figure Presented) Astructurally characterized lower rim 1,3-di{bis(2-picolyl)}amide derivative of calix[4]arene (L) exhibits high selectivity toward Ag+ by forming a 1:1 complex, among nine other biologically important metal ions, viz., Na+, K+, Mg 2+, Ca2+, Mn2+, Fe2+, Co 2+, Ni2+, and Zn2+, as studied by fluorescence, absorption, and 1H NMR spectroscopy. The 1:1 complex formed between L and Ag+ has been further proven on the basis of ESI mass spectrometry and has been shown to have an association constant, Ka, of 11117 ± 190 M-1 based on fluorescence data. L acts as a primary ratiometric sensor toward Ag+ by switch-on fluorescence and exhibits a lowest detectable concentration of 450 ppb. DFT computational studies carried out in mimicking the formation of a 1:1 complex between L and Ag + resulted in a tetrahedral complex wherein the nitrogens of all four pyridyl moieties present on both arms are being coordinated. Whereas these pyridyls are located farther apart in the crystal structure, appropriate dihedral changes are induced in the arms in the presence of silver ion in order to form a coordination complex. Even the nanostructural features obtained in TEM clearly differentiates L from its Ag+ complex. The in situ prepared silver complex of L detects Cys ratiometrically among the naturally occurring amino acids to a lowest concentration of 514 ppb by releasing L from the complex followed by formation of the cysteine complex of Ag+. These were demonstrated on the basis of emission, absorption, 1H NMR, and ESI mass spectra. The INH logic gate has also been generated by choosing Ag + and Cys as input and by monitoring the output signal at 445 nm that originates from the excimer emission of L in the presence of Ag+. Thus L is a potential primary sensor toward Ag+and is a secondary sensor toward Cys. 2009 American Chemical Society.
- Joseph, Roymon,Ramanujam, Balaji,Acharya, Amitabha,Rao, Chebrolu P.
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scheme or table
p. 8181 - 8190
(2010/02/28)
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- The influence of isomerism on the self-assembly behavior and complexation property of 1,3-alternate tetraaminopyridyl-thiacalix[4]arene derivatives
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A series of 1,3-alternate conformation thiacalix[4]arenes containing different isomeric aminopyridyl pendent arms have been synthesized. It was found that their self-assembly behaviors and complexation properties strongly depended on the structures of aminopyridyl pendent arms. The crystal structures demonstrate that tetra(meta-aminopyridyl)-thiacalix[4]arene motif is capable of forming intramolecular hydrogen bondings between the sp2 nitrogen donors in the meta position of the aminopyridyl groups and the facing amide N-H of the adjacent aminopyridyl groups, and self-assembles via C-H?O weak hydrogen bondings and C-H?π interaction to generate a double stranded rectilineal networks. By contrast, in the case of tetra(para-aminopyridyl)-thiacalix[4]arene, the presence of para-aminopyridyl units enables the formation of N-H?N strong hydrogen bondings between the individual molecules leading to the solid-state structure with water-bridged double strands. Their complexation properties had been also studied by measurement of the stability constants for their complexation in a range of metal cations and investigation of their binding models via 1H NMR titration and ESI-MS experiments. It was found that the three ligands exhibited high and selective extractability toward Ag+, and their stoichiometry of ligand to Ag+ was 1:1, while the meta-aminopyridyl derivative showed the best extraction capacity and possessed the most efficient binding sites.
- Li, Xiong,Gong, Shu-Ling,Yang, Wei-Ping,Chen, Yuan-Yin,Meng, Xiang-Gao
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p. 6230 - 6237
(2008/09/21)
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