- A novel jointly colorimetric and fluorescent sensor for Cu2+ recognition and its complex for sensing S2? by a Cu2+ displacement approach in aqueous media
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In this work, a simple and easily synthesized Schiff-based derivative colorimetric and fluorescent sensor (1), 4-dimethylamino-benzoic acid (2-imidazole formaldehyde)-hydrazide, was obtained for the detection of Cu2+ and S2?. The compound 1 exhibited dual spectral responses to Cu2+, that is, vivid color change and fluorescence enhancement in the presence of Cu2+. The detection limits were valued as 0.46 μM and 15 nM according to absorption and fluorescent response, respectively. Both of them are below the World Health Organization (WHO) guidelines for drinking water (31.5 μM). In addition, the ensemble (1-Cu2+) selectively and sensitively detected a low concentration of S2?. As the addition of S2? instantly removed Cu2+ from the ensemble (1-Cu2+) resulting in a color change from yellow to colorless and a “turn-off” fluorescent response. The detection limit for S2? was estimated as 0.12 μM (from fluorescent method) and 0.68 μM (from absorption method), respectively, each of which was also lower than the maximum allowable level of S2? (15 μM) in drinking water defined by the WHO. The binding process was confirmed via UV–vis absorption, fluorescence measurements, 1H NMR, mass spectroscopy and density functional theory calculation. What's more, successful practical application of test paper is used to inspect the S2? which means the convenient and rapid assay in real samples can be achieved.
- Fang, Hao,Huang, Peng-Cheng,Wu, Fang-Ying
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Read Online
- Synthesis and spectral properties of non-symmetrical red and near IR emitter dibenzoBODIPYs
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New symmetrical and non-symmetrical benzoBODIPYs have been synthesized from diketones. For the two series the 3 and 5 positions have been substituted by different aromatic rings and onto benzo sub-units different groups have been introduced. The methodology of diketones self-condensation provides symmetrical dyes. By cross-condensation reaction, these positions can be differentiated and specific functions connected to the desired positions. These molecules have been fully characterized and their optical properties analyzed by both experimental and theoretical means. They are red to NIR emitters with a range of emission from 679 to 780 nm in CH2Cl2. They show maxima of absorption between 651 nm and 732 nm, strong ε of around 100,000 M?1 cm?1 and quite good quantum yields from 16% to 75%. The thienyl moiety on α-positions of the nitrogens generates the highest red shifts. Meanwhile dimethylamino groups in the same positions bring, besides chemical properties, proton sensitive dyes. The bromine atom onto the dibenzo sub-units exhibits good reactivity through Sonogashira coupling reactions. This approach provides multifunctional red to NIR dyes with endless possibilities of combination of chemical properties.
- Khelladi, Mustapha,Leclerc, Nicolas,Jacquemin, Denis,De Nicola, Antoinette,Ulrich, Gilles
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Read Online
- A chromone hydrazide Schiff base fluorescence probe with high selectivity and sensitivity for the detection and discrimination of human serum albumin (HSA) and bovine serum albumin (BSA)
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The discrimination and identification of human serum albumin (HSA) and bovine serum albumin (BSA) is very important, which is due to the vital roles of two SAs in biological and pharmaceutical research. Based on structural screening and docking calculation from a series of homologues, a coumarin Schiff base fluorescent probe 3-hydroxy-N′-((4-oxo-4H-chromen-3-yl)methylene)-2-naphthohydrazide (HCNH) has been designed and synthesized, which could effectively discriminate HSA and BSA. The probe HCNH exhibited superior sensitivity toward HSA and BSA with the detection limits of 10.62 nM and 16.03 nM in PBS solution, respectively. The binding mechanism of HCNH with SAs was studied by Job's plot analysis, SA destruction and displacement assay. Molecular docking and DFT methods were utilized to provide deep insight into the spatial conformation change of HCNH and binding sites in HSA/BSA. The conformation of HCNH was significantly influenced by the microenvironment provided by HSA and BSA, therefore its fluorescence emission was affected correspondingly. Non-toxic probe HCNH could be successfully used for fluorescence bio-imaging of HSA in cancer cells, which is significantly different from normal cells and favors the application in medical diagnosis.
- Fan, Jing,Li, Qing-Zhong,Li, Zhe,Liu, Hai-Bo,Wang, Zhi-Gang,Xie, Cheng-Zhi,Xu, Jing-Yuan,Yan, Xiao-Jing
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- Design, synthesis, in vitro and in vivo evaluation against MRSA and molecular docking studies of novel pleuromutilin derivatives bearing 1, 3, 4-oxadiazole linker
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A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85–110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.
- Liu, Jie,Zhang, Guang-Yu,Zhang, Zhe,Li, Bo,Chai, Fei,Wang, Qi,Zhou, Zi-Dan,Xu, Ling-Ling,Wang, Shou-Kai,Jin, Zhen,Tang, You-Zhi
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- Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof
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The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain and preparation and application thereof The pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain is a compound shown in a formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound, an enantiomer, a diastereoisomer and a tautomer of the compound shown in the formula 2 or the pharmaceutically acceptable salt thereof or a mixture of the solvent compound, the enantiomer, the diastereoisomer and the tautomer in any proportion, including a racemic mixture. The pleuromutilin derivative has good antibacterial activity, is especially suitable for being used as a novel antibacterial agent for systemic system infection of animals or human beings, and has good water solubility.
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Paragraph 0055-0056; 0070; 0090; 0093; 0095; 0103
(2021/07/24)
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- 5-Phenyl-1,3,4-oxadiazol-2(3 H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit
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Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-Triazole 7 as an attractive starting point for a structure-based drug design hit-To-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.
- Mahy, William,Willis, Nicky J.,Zhao, Yuguang,Woodward, Hannah L.,Svensson, Fredrik,Sipthorp, James,Vecchia, Luca,Ruza, Reinis R.,Hillier, James,Kj?r, Svend,Frew, Sarah,Monaghan, Amy,Bictash, Magda,Salinas, Patricia C.,Whiting, Paul,Vincent, Jean-Paul,Jones, E. Yvonne,Fish, Paul V.
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p. 12942 - 12956
(2020/11/13)
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- The development of coumarin Schiff base system applied as highly selective fluorescent/colorimetric probes for Cu2+ and tumor biomarker glutathione detection
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Overexpression of tumor biomarker glutathione (GSH) has been documented in numerous types of cancers, therefor GSH-activated light-up chemosensors for tumor identification require great attention. A new colorimetric/fluorescent probe (7-(diethylamino)-2-oxo-2H-chromen-3-yl)methylene)-4-(dimethylamino) benzohydrazide (HL) was prepared, which could be applied in discriminating Cu2+ and further recognizing GSH based on its Cu complex. Firstly, the probe HL toward Cu2+ exhibited selective fluorescence quenching and obvious color change from yellow to orange-red under visible light. Further, when GSH was introduced to the Cu2+-2HL system, the fluorescence recovered rapidly due to the high affinity of GSH to Cu2+, meanwhile the color reverted back to former yellow. Based on fluorescence titration, the detection limits were calculated as 2.40 × 10?8 M and 1.29 × 10?7 M for Cu2+ and GSH, respectively. The combination mode of HL with Cu2+ was investigated in detail by Job plots, ESI-MS, FT-IR, and DFT studies. Probes HL and Cu2+-2HL showed relatively less toxicity and were employed for biological imaging in cells and zebrafish. Remarkably, the detection for endogenous GSH by this developed sensor platform implied great potential application prospect in cancer diagnosis.
- Wang, Zhi-Gang,Ding, Xiao-Jing,Huang, Yu-Ying,Yan, Xiao-Jing,Ding, Bin,Li, Qing-Zhong,Xie, Cheng-Zhi,Xu, Jing-Yuan
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- A novel one-pot synthesis method of 3,4,5-triaryl-substituted 1,2,4-triazoles
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[Figure not available: see fulltext.] A novel method for the preparation of 3,4,5-triaryl-substituted 1,2,4-triazoles by the reaction of hydrazides with secondary amides in polyphosphoric ester has been developed. The new method is characterized by mild conditions and ease of synthesis, including the stages of isolation and purification of the product. Additionally, product structures were confirmed by counter synthesis. It was shown that the proposed method is suitable for producing 1,2,4-triazoles with phenolic substituents without the stages of the protection and deprotection of the hydroxyl group. Using the new method, five 3,4,5-substituted 1,2,4-triazoles were obtained for the first time.
- Yakuschenko, Igor K.,Pozdeeva, Natal’ya N.,Gadomsky, Svyatoslav Ya.
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p. 834 - 838
(2019/11/14)
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- SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents
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Recently, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for drug discovery of next-generation antifungal agents, and we found two aromatic acylhydrazones as effective inhibitors of GlcCer synthesis based on HTP screening. In the present work, we have designed libraries of new aromatic acylhydrazones, evaluated their antifungal activities (MIC80 and time-kill profile) against C. neoformans, and performed an extensive SAR study, which led to the identification of five promising lead compounds, exhibiting excellent fungicidal activities with very large selectivity index. Moreover, two compounds demonstrated broad spectrum antifungal activity against six other clinically relevant fungal strains. These five lead compounds were examined for their synergism/cooperativity with five clinical drugs against seven fungal strains, and very encouraging results were obtained; e.g., the combination of all five lead compounds with voriconazole exhibited either synergistic or additive effect to all seven fungal strains.
- Del Poeta, Maurizio,Haranahalli, Krupanandan,Lazzarini, Cristina,Mallamo, John,McCarthy, J. Brian,Ojima, Iwao,Pathiranage, Senuri,Sun, Yi,Zambito, Julia
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- Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents
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4-(Nitrophenyl)hydrazone derivatives of N-acylhydrazone were synthesized and screened for suppress lymphocyte proliferation and nitrite inhibition in macrophages. Compared to an unsubstituted N-acylhydrazone, active compounds were identified within initial series when hydroxyl, chloride and nitro substituents were employed. Structure-activity relationship was further developed by varying the position of these substituents as well as attaching structurally-related substituents. Changing substituent position revealed a more promising compound series of anti-inflammatory agents. In contrast, an N-methyl group appended to the 4-(nitrophenyl)hydrazone moiety reduced activity. Anti-inflammatory activity of compounds is achieved by modulating IL-1β secretion and prostaglandin E2 synthesis in macrophages and by inhibiting calcineurin phosphatase activity in lymphocytes. Compound SintMed65 was advanced into an acute model of peritonitis in mice, where it inhibited the neutrophil infiltration after being orally administered. In summary, we demonstrated in great details the structural requirements and the underlying mechanism for anti-inflammatory activity of a new family of hydrazone-N-acylhydrazone, which may represent a valuable medicinal chemistry direction for the anti-inflammatory drug development in general.
- Meira, Cássio S.,dos Santos Filho, José Maurício,Sousa, Caroline C.,Anjos, Pamela S.,Cerqueira, Jéssica V.,Dias Neto, Humberto A.,da Silveira, Rafael G.,Russo, Helena M.,Wolfender, Jean-Luc,Queiroz, Emerson F.,Moreira, Diogo R.M.,Soares, Milena B.P.
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p. 1971 - 1985
(2018/03/12)
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- Preparation method and applications of permanently charged hydrazine-based saccharide marker
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The invention relates to a preparation method of a permanently charged hydrazine-based saccharide marker, and belongs to the technical field of organic synthesis and bioinformation, wherein benzocaine is subjected to a series of synthesis to prepare the permanently charged hydrazine-based saccharide marker. According to the present invention, the reaction conditions (5% acetic acid, 80 DEG C and 3 h) of the prepared permanently charged hydrazine-based saccharide marker are mild so as to remarkably improve the sensitivity; and after the reaction, the detection can be performed directly with high performance liquid chromatography and mass spectrometry (ESI-MS, MALDI-ToF-MS) without further purification, and the sensitivity is good.
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Paragraph 0021
(2018/01/12)
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- Combretastatin linked 1,3,4-oxadiazole conjugates as a Potent Tubulin Polymerization inhibitors
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A new class of combretastatin linked 1,3,4-oxadiazoles were designed, synthesized and screened for their cytotoxic activity against five human cancer cell lines such as HeLa, DU-145, A549, MDA-MB-231 and B16. These compounds showed significant cytotoxicity with IC50 values in the range 0.118-54.32 μM. Conjugate 5m displayed potent antiproliferative activity against DU-145 cell line. Flow cytometric analysis revealed that these compounds arrested the cell cycle in G2/M phase. Moreover, the tubulin polymerization assay and immunofluorescence analysis indicate that 5m exhibits potent inhibitory effect on the tubulin assembly. Further, DNA fragmentation and Hoecst staining assays confirm that 5m induces apoptosis. Molecular docking studies and competitive binding assay indicated that 5m effectively bind at the colchicine binding site of the tubulin.
- Kamal, Ahmed,Srikanth,Vishnuvardhan,Kumar, G. Bharath,Suresh Babu, Korrapati,Hussaini, S.M. Ali,Kapure, Jeevak Sopanrao,Alarifi, Abdullah
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p. 126 - 136
(2016/03/09)
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- Design, Synthesis, and Pharmacological Evaluation of Novel N-Acylhydrazone Derivatives as Potent Histone Deacetylase 6/8 Dual Inhibitors
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This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6/8 than their meta analogs. In addition, the effect of compounds (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazono)methyl)-N-hydroxybenzamide (3c) and (E)-4-((2-(4-(dimethylamino)benzoyl)-2-methylhydrazono)methyl)-N-hydroxybenzamide (3f) on the acetylation of α-tubulin revealed an increased level of acetylation. These two compounds also affected cell migration, indicating their inhibition of HDAC6. An analysis of the antiproliferative activity of these compounds, which presented the most potent activity, showed that compound 3c induced cell cycle arrest and 3g induced apoptosis through caspase 3/7 activation. These results suggest HDAC6/8 as a potential target of future molecular therapies for cancer.
- Rodrigues, Daniel A.,Ferreira-Silva, Guilherme à.,Ferreira, Ana C. S.,Fernandes, Renan A.,Kwee, Jolie K.,SantAnna, Carlos M. R.,Ionta, Marisa,Fraga, Carlos A. M.
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p. 655 - 670
(2016/02/05)
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- Acylhydrazones as Widely Tunable Photoswitches
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Molecular photoswitches have attracted much attention in biological and materials contexts. Despite the fact that existing classes of these highly interesting functional molecules have been heavily investigated and optimized, distinct obstacles and inherent limitations remain. Considerable synthetic efforts and complex structure-property relationships render the development and exploitation of new photoswitch families difficult. Here, we focus our attention on acylhydrazones: a novel, yet underexploited class of photochromic molecules based on the imine structural motif. We optimized the synthesis of these potent photoswitches and prepared a library of over 40 compounds, bearing different substituents in all four crucial positions of the backbone fragment, and conducted a systematic study of their photochromic properties as a function of structural variation. This modular family of organic photoswitches offers a unique combination of properties and the compounds are easily prepared on large scales within hours, through an atom-economic synthesis, from commercially available starting materials. During our thorough spectroscopic investigations, we identified photoswitches covering a wide range of thermal half-lives of their (Z)-isomers, from short-lived T-type to thermally stable P-type derivatives. By proper substitution, excellent band separation between the absorbance maxima of (E)- and (Z)-isomers in the UV or visible region could be achieved. Our library furthermore includes notable examples of rare negative photochromic systems, and we show that acylhydrazones are highly fatigue resistant and exhibit good quantum yields.
- Van Dijken, Derk Jan,Kova?í?ek, Petr,Ihrig, Svante P.,Hecht, Stefan
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supporting information
p. 14982 - 14991
(2015/12/08)
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- Synthesis of 5-substituted-3H-[1,3,4]-oxadiazol-2-one derivatives: A carbon dioxide route (CDR)
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A carbon dioxide route (CDR) for making biologically important 5-substituted-3H-[1,3,4]-oxadiazol-2-ones (SHOs) has been accomplished through synthesis and cyclization of a variety of hydrazides as the key intermediates. All of these hydrazides were prepared readily in 89-97% yields by reacting acid chlorides with a hydrazine monohydrate in the initial step. Then, SHOs were obtained in high yields from hydrazides by reacting them with carbon dioxide under basic conditions. More notable than the high yields, is that the present CDR process for the first time has succeeded in providing a straightforward cyclization reaction leading to SHO formation with simple reagents in ethanol solution.
- Brahmayya,Dai, Shenghong A.,Suen
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p. 65351 - 65357
(2015/08/18)
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- Designing and exploring active N′-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients
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Chagas disease affects around 8 million people worldwide and its treatment depends on only two nitroheterocyclic drugs, benznidazole (BZD) and nifurtimox (NFX). Both drugs have limited curative power in chronic phase of disease. Nifuroxazide (NF), a nitroheterocyclic drug, was used as lead to design a set of twenty one compounds in order to improve the anti-Trypanosoma cruzi activity. Lipinski's rules were considered in order to support drug-likeness designing. The set of N′-[(5-nitrofuran-2-yl) methylene] substituted hydrazides was assayed against three T. cruzi strains, which represent the discrete typing units more prevalent in human patients: Y (TcII), Silvio X10 cl1 (TcI), and Bug 2149 cl10 (TcV). All the derivatives, except one, showed enhanced trypanocidal activity against the three strains as compared to BZD. In the Y strain 62% of the compounds were more active than NFX. The most active compound was Ng€2-((5-nitrofuran-2-yl) methylene)biphenyl-4-carbohydrazide (C20), which showed IC50 values of 1.17 ± 0.12 μM; 3.17 ± 0.32 μM; and 1.81 ± 0.18 μ4M for Y, Silvio X10 cl1, and Bug 2149 cl10 strains, respectively. Cytotoxicity assays with human fibroblast cells have demonstrated high selectivity indices for several compounds. Exploratory data analysis indicated that primarily topological, steric/geometric, and electronic properties have contributed to the discrimination of the set of investigated compounds. The findings can be helpful to drive the designing, and subsequently, the synthesis of additional promising drugs against Chagas disease.
- De Azevedo, Ricardo Alexandre,Ferreira, Adilson Kleber,Jorge, Salomo Dria,Palace-Berl, Fanny,Pasqualoto, Kerly Fernanda Mesquita,Silva, Marcelo Nunes,Tavares, Leoberto Costa,Teixeira, Sarah Fernandes,Zingales, Bianca,Zorzi, Rodrigo Rocha
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p. 330 - 339
(2015/04/27)
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- The α-effect in hydrazinolysis of 4-chloro-2-nitrophenyl x-substituted-benzoates: Effect of substituent x on reaction mechanism and the α-effect
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Second-order rate constants (kN) have been measured spectrophotometrically for the reaction of 4-chloro-2- nitrophenyl X-substituted-benzoates (6a-6h) with a series of primary amines including hydrazine in 80 mol % H2O/20 mol % DMSO at 25.0°C. The Bronsted-type plot for the reaction of 4-chloro-2-nitrophenyl benzoate (6d) is linear with βnuc = 0.74 when hydrazine is excluded from the correlation. Such a linear Bronsted-type plot is typical for reactions reported previously to proceed through a stepwise mechanism in which expulsion of the leaving group occurs in the rate-determining step (RDS). The Hammett plots for the reactions of 6a-6h with hydrazine and glycylglycine are nonlinear. In contrast, the Yukawa-Tsuno plots exhibit excellent linear correlations with ?X = 1.29-1.45 and r = 0.53-0.56, indicating that the nonlinear Hammett plots are not due to a change in RDS but are caused by resonance stabilization of the substrates possessing an electron-donating group (EDG). Hydrazine is ca. 47-93 times more reactive than similarly basic glycylglycine toward 6a-6h (e.g., the α-effect). The α-effect increases as the substituent X in the benzoyl moiety becomes a stronger electronwithdrawing group (EWG), indicating that destabilization of the ground state (GS) of hydrazine through the repulsion between the nonbonding electron pairs on the two N atoms is not solely responsible for the substituent-dependent α-effect. Stabilization of transition state (TS) through five-membered cyclic TSs, which would increase the electrophilicity of the reaction center or the nucleofugality of the leaving group, contributes to the α-effect observed in this study.
- Kim, Min-Young,Kim, Tae-Eun,Lee, Jieun,Um, Ik-Hwan
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p. 2271 - 2276
(2014/09/29)
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- Kinetic study on nucleophilic displacement reactions of 2-chloro-4-nitrophenyl x-substituted-benzoates with primary amines: Reaction mechanism and origin of the a-effect
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Second-order rate constants for aminolysis of 2-chloro-4-nitrophenyl X-substituted-benzoates (1a-h) have been measured spectrophotometrically in 80 mol % H2O/20 mol % DMSO at 25.0 °C. The Bronsted-type plot for the reactions of 2-chloro-4-nitrophenyl benzoate (1d) with a series of primary amines curves downward, which has been taken as evidence for a stepwise mechanism with a change in rate-determining step (RDS). The Hammett plots for the reactions of 1a-h with hydrazine and glycylglycine are nonlinear while the Yukawa- Tsuno plots exhibit excellent linearity with ρX = 1.22-1.35 and r = 0.57-0.59, indicating that the nonlinear Hammett plots are not due to a change in RDS but are caused by stabilization of substrates possessing an electron-donating group (EDG) through resonance interactions between the EDG and C=O bond of the substrates. The α-effect exhibited by hydrazine increases as the substituent X changes from a strong EDG to a strong electron-withdrawing group (EWG). It has been concluded that destabilization of hydrazine through the electronic repulsion between the adjacent nonbonding electrons is not solely responsible for the substituent dependent α-effect but stabilization of the transition state is also a plausible origin of the α-effect.
- Um, Tae-Il,Kim, Min-Young,Kim, Tae-Eun,Um, Ik-Hwan
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p. 436 - 440
(2014/03/21)
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- Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents
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A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7 ± 0.2, 30.0 ± 1.2, 18.3 ± 1.4 μM, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 μM, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 μg/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.
- Du, Qian-Ru,Li, Dong-Dong,Pi, Ya-Zhou,Li, Jing-Ran,Sun, Jian,Fang, Fei,Zhong, Wei-Qing,Gong, Hai-Bin,Zhu, Hai-Liang
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p. 2286 - 2297
(2013/05/09)
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- Synthesis, biological evaluation and molecular docking studies of novel 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives
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In present study, a series of new 2-(1,3,4-oxadiazol-2-ylthio)-1- phenylethanone derivatives (6a-6x) as potential focal adhesion kinase (FAK) inhibitors were synthesized. The bioassay assays demonstrated that compound 6i showed the most potent activity, which inhibited the growth of MCF-7 and A431 cell lines with IC50 values of 140 ± 10 nM and 10 ± 1 nM, respectively. Compound 6i also exhibited significant FAK inhibitory activity (IC50 = 20 ± 1 nM). Docking simulation was performed to position compound 6i into the active site of FAK to determine the probable binding model.
- Zhang, Li-Rong,Liu, Zhi-Jun,Zhang, Hui,Sun, Jian,Luo, Yin,Zhao, Ting-Ting,Gong, Hai-Bin,Zhu, Hai-Liang
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scheme or table
p. 3615 - 3621
(2012/07/27)
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- Configurational and constitutional information storage: Multiple dynamics in systems based on pyridyl and acyl hydrazones
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The C=N group of hydrazones can undergo E/Z isomerization both photochemically and thermally, allowing the generation of a closed process that can be tuned by either of these two physical stimuli. On the other hand, hydrazine-exchange reactions enable a constitutional change in a given hydrazone. The two classes of processes: 1) configurational (physically stimulated) and 2) constitutional (chemically stimulated) give access to short-term and long-term information storage, respectively. Such transformations are reported herein for two hydrazones (bis-pyridyl hydrazone and 2-pyridinecarboxaldehyde phenylhydrazone) that undergo a closed, chemically or physically driven process, and, in addition, can be locked or unlocked at will by metal-ion coordination or removal. These features also extend to acyl hydrazones derived from 2-pyridinecarboxaldehyde. Similarly to the terpydine-like hydrazones, such acyl hydrazones can undergo both constitutional and configurational changes, as well as metal-ion coordination. All these types of hydrazones represent dynamic systems capable of acting as multiple state molecular devices, in which the presence of coordination sites furthermore allows the metal ion-controlled locking and unlocking of the interconversion of the different states.
- Chaur, Manuel N.,Collado, Daniel,Lehn, Jean-Marie
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scheme or table
p. 248 - 258
(2011/03/21)
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- 17O NMR studies of substituted 1,3,4-oxadiazoles
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Three series of substituted 1,3,4-oxadiazoles were studied by 17O NMR spectroscopy. Chemical shifts values were correlated with empirical Hammett parameters as well as calculated bond lengths and chemical shielding values.
- Gierczyk, Blazej,Zalas, MacIej,Kazmierczak, Marcin,Grajewski, Jakub,Pankiewicz, Radoslaw,Wyrzykiewicz, Bozena
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scheme or table
p. 648 - 654
(2012/01/06)
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- Synthesis, biological evaluation, and molecular docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents
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A series of new 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety were synthesized. Antiproliferative assay results indicated that compounds 6o and 6u exhibited the most potent activity against gastric cancer cell SGC-7901, which was more potent than the positive control. Especially, compound 6o exhibited significant telomerase inhibitory activity (IC 50 = 2.3 ± 0.07 μM), which was comparable to the positive control ethidium bromide. Docking simulation was performed to position compound 6o into the active site of telomerase (3DU6) to determine the probable binding model.
- Zheng, Qing-Zhong,Zhang, Xiao-Min,Xu, Ying,Cheng, Kui,Jiao, Qing-Cai,Zhu, Hai-Liang
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scheme or table
p. 7836 - 7841
(2011/01/13)
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- Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus
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Molecular modification is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N′-(benzofuroxan-5-yl)methylene]benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological profile. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF3 substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 μg/mL, and a Clog P value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates.
- Jorge, Salomao Doria,Masunari, Andrea,Rangel-Yagui, Carlota Oliveira,Pasqualoto, Kerly Fernanda Mesquita,Tavares, Leoberto Costa
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experimental part
p. 3028 - 3036
(2009/09/08)
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- Synthesis and anti-inflammatory activity of 4-substituted-2,5-disubstituted indolyl azetidine-3-yl/thiazolidin-1-yl-substituted triazoles
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A new series of 4-[2′-(substituted phenyl)-5′-methoxy indolyl azetidine-l-yl/thiazolin-1-yl-3-(substituted phenyl)-5-mercapto-l,2,4-triazoles were designed, synthesized and tested for anti-inflammatory and analgesic activities. All compounds were screened in vitro for anti-inflammatory activity against carrageenan induced rat paw oedema and tested for their analgesic activity against phenyl quinone induced pain syndrome in mice at a dose of 50 mg/kg p.o. All the compounds of this series have been analyzed and confirmed by elemental (C, H, N) and spectral methods, i.e. I.R., 1HNMR, 13C NMR and mass spectrometry data.
- Chandra, Trilok,Garg, Neha,Kumar, Ashok
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experimental part
p. 243 - 252
(2010/08/07)
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- Studies on synthesis and pharmacological activities of 1,2,4- triazolo[3,4-b]1,3,4-thiadiazoles and their dihydro analogues
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4-Amino-5-substituted aryl-3-mercapto-1,2,4-triazoles are versatile synthons for constructing various biologically active heterocycles. Starting from 4-amino-5-substituted aryl-3-mercapto-1,2,4- triazole 3a-c, a series of new 3,5-disubstituted-1,2,4-triazolo-[3,4-b]1,3,4-thiadiazoles and their 5,6-dihydrotriazolothiadiazoles were prepared. The structures of all the newly synthesized compounds have been confirmed by elemental analysis, IR, 1H-NMR, 13C-NMR, and mass spectra. The antimicrobial effects of the synthesized compounds were investigated using the paper disc method. Anti-inflammatory and analgesic activities of the synthesized compounds were assessed by carrageenan-induced rat paw oedema method and by Eddy's hot plate method, respectively. Some of the compounds exhibited promising antimicrobial activities as well as moderate to good anti-inflammatory activity and analgesic activity.
- Mathew, Vinod,Giles, Devasahayam,Keshavayya, Jathi,Vaidya, Vijaya P.
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experimental part
p. 210 - 222
(2009/05/27)
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- An intramolecular charge transfer fluorescent probe: Synthesis and selective fluorescent sensing of Ag+
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An intramolecular charge transfer (ICT) fluorescent probe, in which the thiourea derivative moiety is linked to the fluorescent 4-(dimethylamino) benzamide, has been designed and synthesized. The ions-selective signaling behaviors of the probe were investigated. Upon the addition of Ag+, an overall emission enhancement of 14-fold was observed. Compound 1 displayed highly selective chelation enhanced fluorescence (CHEF) effect with Ag+ over alkali, alkali earth metal ions and some transition metal ions in aqueous methanol solutions. The prominent selective and efficient fluorescent enhancing behavior could be utilized as a new chemosensing probe for the analysis of Ag+ ion in aqueous environment.
- Mu, Honglei,Gong, Rui,Ren, Lin,Zhong, Cheng,Sun, Yimin,Fu, Enqin
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experimental part
p. 923 - 928
(2009/01/31)
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- Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides
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A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC50 values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites.
- Rando, Daniela G.,Avery, Mitchell A.,Tekwani, Babu L.,Khan, Shabana I.,Ferreira, Elizabeth I.
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p. 6724 - 6731
(2008/12/22)
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- Keto-1,3,4-oxadiazoles as cathepsin K inhibitors
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We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P1, P2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis.
- Palmer, James T.,Hirschbein, Bernard L.,Cheung, Harry,McCarter, John,Janc, James W.,Yu, Z. Walter,Wesolowski, Gregg
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p. 2909 - 2914
(2008/09/21)
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- Potential tuberculostatic agents. Topliss application on benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazide series.
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Nitroaromatic compounds such as nifuroxazide are used in many human enteropathogenic bacteria infections without causing an increase in the plasmidial antibiotic resistance of the aerobic Gram-negative intestinal Enterobacteriaceae. For these reasons, these compounds have been synthesized using the rational approach of Topliss' decision tree. Generally, this approach allows us to obtain the most active derivative from the series in a few steps. These compounds were tested against Mycobacterium tuberculosis in vitro and the most active of the series identified. A new lead for potential tuberculostatic activity has been predicted and will be used in further QSAR studies.
- Rando, Daniela G,Sato, Dayse N,Siqueira, Leonardo,Malvezzi, Alberto,Leite, Clarice Q F,do Amaral, Antonia T,Ferreira, Elizabeth I,Tavares, Leoberto C
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p. 557 - 560
(2007/10/03)
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- New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models
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During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.
- Szczepankiewicz,Chiou,Credo,Alder,Nukkala,Zielinski,Jarvis,Mollison,Frost,Bauch,Hui,Liu,Claiborne,Li,Rosenberg,Jae,Tasker,Gunawardana,Von Geldern,Gwaltney II,Wu-Wong,Gehrke
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p. 4416 - 4430
(2007/10/03)
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- Synthesis and biological activity of nifuroxazide and analogs
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Nifuroxazide and thirteen analogs were synthesized from substituted benzoic acids and minimal inhibitory concentrations were determined using the serial dilution tests, in three sequential steps. Nifuroxazide and chloramphenicol were used as reference standards. The tests were performed in TSB against the standard bacterial strain of Staphylococcus aureus ATCC 25923.
- Tavares,Penna,Amaral
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p. 244 - 249
(2007/10/03)
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- Blue electroluminescent 1,2,4-triazole derivative
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A blue fluorescent 1,2,4-triazole derivative, DA-TAZ, was synthesized and examined as an emitter layer in organic electroluminescent device. The device structure of glass substrate / indium- tin oxide / hole-transporting diamine layer / DA-TAZ layer / Mg:Ag was employed. The EL device exhibited bright blue light originating from the DA-TAZ emitter layer with a maximum luminance of 1200 cd/m2 at 14 volt.
- Kido, Junji,Kimura, Masato,Nagai, Katsutoshi
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