- Structure Activity Relationship of 4-Phenyl-1-(1-Acylindolin-5-Ylsulfonyl)Pyrrolidin-2-Ones on Anticancer Activity
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Microtubules play a dynamic role during cell division. In our early studies 4-phenyl-1-(1-acylindoline-5-sulfonylimidazolones were thoroughly explored and found that the indoline bicyclic system next to the sulfonyl group is very important for cytotoxicity. In this research, imidazolone motif was replaced with pyrrolidin-2-one and this isosteric replacement led to show some promising activity. Thus, the structure activity relationship of 4-phenyl-1-(1-acylindolin-5-ylsulfonyl)pyrrolidin-2-ones with the various acyl group at the indoline NH was explored. The presence of benzoyl groups with electron donating group was the more favorable for cytotoxicity while less bulky alkanoyl groups led to decrease cytotoxicity.
- Subramanian, Santhosh,Boggu, Pulla Reddy,Yun, Jieun,Jung, Sang-Hun
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Read Online
- Design and synthesis of N-(3-sulfamoylphenyl)amides as Trypanosoma brucei leucyl-tRNA synthetase inhibitors
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The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC50 of 0.24 and 0.25 μM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.
- Li, Zezhong,Xin, Weixiang,Wang, Qing,Zhu, Mingyan,Zhou, Huchen
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- Hydroxybenzoyl Chlorides in the Synthesis of Conjugates with Biologically Active Dipeptides
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Abstract: Conjugates of hydroxy- and acetoxybenzoic acids with dipeptides based on 4-aminobutanoic acid and glycine were synthesized through hydroxy(acetoxy)benzoyl chlorides and 4-[hydroxy(acetoxy)benzoyl-amino]butanoyl chlorides as intermediate products. Acyl chlorides were prepared by treatment of the corre-sponding acids with oxalyl chloride in the presence of dimethylformamide at a ratio of 1:1.1:0.07 in boiling benzene. The target N-[hydroxy(acetoxy)benzoyl] derivatives of dipeptides were obtained with high yields, and no further purification of the products was necessary. The synthesized compounds were evaluated as potential neuroprotective agents.
- Brel, A. K.,Budaeva, Yu. N.,Lisina, S. V.
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p. 540 - 544
(2021/06/02)
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- DIRECTED CONJUGATION TECHNOLOGIES
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Among other things, the present disclosure provides technologies for site-directed conjugation of various moieties of interest to target agents. In some embodiments, the present disclosure utilizes target binding moieties to provide high conjugation efficiency and selectivity. In some embodiments, provided technologies are useful for preparing antibody conjugates.
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Paragraph 0755
(2021/05/29)
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- Synthesis and Fungitoxic Evaluation of Acylamino-1,2,4-Triazoles
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Ten different acylamino-1,2,4-triazoles were prepared by the reaction of differently substituted benzoyl chlorides and acetyl chlorides with 4-amino-1,2,4-triazole using catalytic amount of triethylamine. The synthesized compounds were characterized using UV, 1H-nuclear magnetic resonance spectroscopy, and infrared spectroscopy. All the compounds were tested for their fungicidal potential against three fungal species, that is, Fusarium verticillioides, Macrophomina phaseolina, and Rhizoctonia solani using poisoned food technique. The synthesized compounds were tested at various concentrations along with standard carbendazim 50 WP. The amides synthesized by reaction of substituted benzoyl chlorides and 4-amino-1,2,4-triazole exhibited greater fungicidal activity against all the tested fungi as compared to the amides synthesized using substituted acetyl chlorides. Among all the tested compounds, 4-nitro-N-(4-H-1,2,4-triazol-4-yl)benzamide showed the maximum fungicidal activity with the least median effective dose (ED50) values of 100, 93, and 146 μg ml-1 against F verticillioides, M. phaseolina, and R. solani, respectively. All the compounds were found to be less effective than the standard used.
- Kaur, Gurinderjit,Kaur, Harleen,Kaur, Pardeep,Sharma, Sunita,Singh, Ravneet
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p. 389 - 395
(2021/11/22)
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- Synthesis of novel liquid crystalline and fire retardant molecules based on six-armed cyclotriphosphazene core containing Schiff base and amide linking units
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Nucleophilic substitution reaction between 4-hydroxybenzaldehyde and hexachlorocyclotriphosphazene, HCCP formed hexakis(4-formlyphenoxy)cyclotriphosphazene, 1. Intermediates 2a-e was formed from the alkylation reaction of methyl 4-hydroxybenzoate with alkyl bromide which further reduced to form benzoic acid intermediates. Further reaction of 2a-e and other substituted benzoic acid formed 3a-h, which then reduced to give subsequent amines, 4a-h. Other similar reaction was used to synthesis 4i. Condensation reaction between 1 and 4a-i yielded hexasubstituted cyclotriphosphazene compounds, 5a-i having Schiff base and amide linking units, and these compounds consist of different terminal substituents such as heptyl, nonyl, decyl, dodecyl, tetradecyl, hydroxy, carboxy, chloro, and nitro groups, respectively. Compound 5j with amino substituent at terminal end was formed from the reduction of 5i. All the intermediates and compounds were characterized using Fourier Transform Infrared (FT-IR), Nuclear Magnetic Resonance (NMR) and CHN elemental analysis. Mesophase texture of these compounds were determined using Polarized Optical Microscope (POM) and their mesophase transition were further confirmed using Differential Scanning Calorimetry (DSC). Only compounds 5a-e with alkoxy chains exhibited smectic A phase while other intermediates (1, 2a-e, 3a-h, and 4a-i) and final compounds (5f-j) are found to be non-mesogenic with no liquid crystal behaviour. The confirmation of the identity of the SmA phase was determined using XRD analysis. The study on the structure-properties relationship was conducted in order to determine the effect of the terminal group, length of the chains and linking units to the mesophase behaviour of the compounds. Moreover, the fire retardant properties of these compounds were determined using Limiting Oxygen Index (LOI) testing. Polyester resin with LOI value of 22.53% was used as matrix for moulding in the study. The LOI value increased to 24.71% when this polyester resin incorporated with 1 wt% of HCCP. Generally, all the final compounds showed a positive results with LOI value above 27% and the highest LOI value was belonged to compound 5i with 28.53%. The high thermal stability of the Schiff base molecules and the electron withdrawing group of the amide bonds and nitro group enhanced the fire retardant properties of this compound.
- Guan-Seng, Tay,Jamain, Zuhair,Khairuddean, Melati
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p. 28918 - 28934
(2020/08/25)
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- Meta -Substituted benzenesulfonamide: A potent scaffold for the development of metallo-β-lactamase ImiS inhibitors
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Metallo-β-lactamase (MβL) ImiS contributes to the emergence of carbapenem resistance. A potent scaffold, meta-substituted benzenesulfonamide, was constructed and assayed against MβLs. The twenty-one obtained molecules specifically inhibited ImiS (IC50 = 0.11-9.3 μM); 2g was found to be the best inhibitor (IC50 = 0.11 μM), and 1g and 2g exhibited partially mixed inhibition with Ki of 8.0 and 0.55 μM. The analysis of the structure-activity relationship revealed that the meta-substitutes improved the inhibitory activity of the inhibitors. Isothermal titration calorimetry (ITC) assays showed that 2g reversibly inhibited ImiS. The benzenesulfonamides exhibited synergistic antibacterial effects against E. coli BL21 (DE3) cells with ImiS, resulting in a 2-4-fold reduction in the MIC of imipenem and meropenem. Also, mouse experiments showed that 2g had synergistic efficacy with meropenem and significantly reduced the bacterial load in the spleen and liver after a single intraperitoneal dose. Tracing the ImiS in living E. coli cells by RS at a super-resolution level (3D-SIM) showed that the target was initially associated on the surface of the cells, then there was a high density of uniform localization distributed in the cytosol of cells, and it finally accumulated in the formation of inclusion bodies at the cell poles. Docking studies suggested that the sulfonamide group acted as a zinc-binding group to coordinate with Zn(ii) and the residual amino acid within the CphA active center, tightly anchoring the inhibitor at the active site. This study provides a highly promising scaffold for the development of inhibitors of ImiS, even the B2 subclasses of MβLs.
- Chen, Cheng,Gao, Han,Liu, Ya,Sun, Le-Yun,Yang, Ke-Wu,Zhen, Jian-Bin
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p. 259 - 267
(2020/04/17)
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- Design, synthesis and biological activity evaluation of a new class of 2,4-thiazolidinedione compounds as insulin enhancers
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Diabetes mellitus (DM) is a global disease with a high incidence of type 2 diabetes. Current studies have shown that insulin enhancers play an important role in the treatment of type 2 diabetes and have great importance in the improvement of type 2 diabetes. In this research, Rosiglitazone was taken as the lead compound, and the structure was modified by using the bioisostere principle, and a new class of 2,4-thiazolanedione compound was designed and synthesised. The novel series of compounds were studied for their biological activities in vitro and in vivo. In vitro tests, the biological activities showed that the target compounds have good selective activation of peroxisome-proliferator-activated receptor γ (PPARγ), such as the compounds 6a, 6e, 6f, 6g and 6i, especially the compound 6e to PPARγ was EC50 = 0.03 ± 0.01 μmol/L in vitro. Then, in vivo biological activities’ test results showed that the tendency of increasing in blood sugar had an obvious inhibiting effect, and had a significant insulin hypoglycaemic effect of enhancing and extending the exogenous. In addition, the results of cytotoxicity tests and acute toxicity tests (LD50) showed that these compounds belong to the low toxicity compounds.
- Huiying, Zou,Guangying, Chen,Shiyang, Zhou
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p. 981 - 989
(2019/05/21)
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- Uracil Hydroxybenzamides as Potential Antidiabetic Prodrugs
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A series of N1, N3-bis-hydroxybenzoyl, -acetoxybenzoyl, and -methoxybenzoyl uracil derivatives were synthesized. All compounds were screened for the ability to rupture protein cross links and antiglycating, chelating, and antiaggregant properties, which are most significant for pharmacological treatment of thrombosis and angio-, nephro-, encephalo-, and cardiopathies. 1,3-bis-(4-Methoxybenzoyl)pyrimidine-2,4(1H,3H)-dione was a promising antidiabetic agent with all studied activities.
- Brel’,Spasov,Lisina,Popov,Kucheryavenko,Litvinov,Salaznikova,Rashchenko
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p. 511 - 515
(2019/11/22)
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- Novel preparation method of 4-hydroxybenzene formyl chloride
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The invention discloses a novel preparation method of 4-hydroxybenzene formyl chloride as follows as shown in the specification and belongs to the technical field of pharmaceutical technologies. The invention aims at relating to the more advanced novel preparation method of 4-hydroxybenzene formyl chloride. The invention aims at providing the novel preparation method of the compound.
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-
Paragraph 0007; 0008; 0009; 0010
(2018/11/22)
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- Polymerizable compound, preparation method thereof and display device
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The invention provides a polymerizable compound, a preparation method thereof and a display device and relates to the field of liquid crystal display. The polymerizable compound is suitable for use asa reactive mesocrystal and is used for increasing the response speed of a liquid crystal molecule in a liquid crystal medium in which a polymer is stably oriented. The polymerizable compound has a structural general formula as shown in the specification. The invention relates to an application of the polymerizable compound to the liquid crystal medium.
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Paragraph 0087; 0092
(2018/06/26)
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- Synthesis and antibacterial activity of C-7 acylhydrazone derivatives of dehydroabietic acid
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Seven new C-7 acylhydrazone derivatives of dehydroabietic acid were synthesised from dehydroabietic acid through benzylic oxidation, condensation with hydrazine hydrate, followed by nucleophilic substitution reactions with a variety of substituted aromatic acids. The structures of the synthesised compounds were characterised by IR, 1H NMR and MS. The antibacterial activities of the synthesised compounds were evaluated by the disk diffusion method. Antibacterial activity studies showed that C-7 acylhydrazone derivatives of dehydroabietic acid exhibited inhibitory activities against Escherichia coli, Staphylococcus aureus and Bacillus subtilis. Among the seven compounds, dehydroabietic acid p-fluorobenzoyl hydrazone showed the strongest inhibitory activity against B. subtilis and S. aureus.
- Zhou, Zhi,Zhou, Tingting
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p. 405 - 407
(2018/09/12)
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- COMPOUNDS AND METHODS FOR REGULATING INSULIN SECRETION
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Disclosed herein are methods for inducing insulin secretion in a glucose-dependent manner and compounds for use in these methods.
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Page/Page column 123
(2018/10/19)
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- Evaluation of N-Hydroxy-, N-Metoxy-, and N-Acetoxybenzoyl-Substituted Derivatives of Thymine and Uracil as New Substances for Prevention and Treatment of Long-Term Complications of Diabetes Mellitus
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New uracil and thymine derivatives, N1-,N3- and N1,N3-(RO-benzoyl)-(1H,3H)-pyrimidine- 2,4-diones, were synthesized (RO- is hydroxy, acetoxy- or methoxy-group). The compounds were studied in a complex of in vitro tests for the ability to inhibit the development of long-term complications of diabetes. Their ability to cleave cross-links of proteins has been evaluated. The most significant ways of pharmacological correction of thrombosis, angio-, nephro-, encephalo-, and cardiopathy, antiglycation, chelating, and antiplatelet activities, have been established. The most active compound in terms of antiplatelet action, N1- hydroxybenzoyluracil, exceeded acetylsalicylic acid by ~44%. In terms of their ability to chelate copper (II) cations, all compounds (with the exception of 1,3-bis(3-hydroxybenzoyl)-(1H,3H)-pyrimidine-2,4-dione that was not not studied in this test) showed the activity, whose IC50 fell in the range between that for pioglitazone (44.1 μM) and pyridoxamine (136.7 μM) comparison drugs. The best antiglycation effect at the 1 mM concentration was observed for N1,N3-bismethoxy- and N1,N3-bisacetoxybenzoyl derivatives of thymine. The maximum activity to cleave cross-links of proteins (C = 1 mM), comparable to that of alagebrium, was established for 1,3-bis(4-methoxybenzoyl)uracil, for which also high rates of other estimated activities were noted. Thus, the N1-,N3- and N1,N3-(RO-benzoyl) derivatives of uracil and thymine are promising basiсs for creating drugs that suppress the development of long-term complications of diabetes.
- Spasov,Brel,Litvinov,Lisina,Kucheryavenko,Budaeva, Yu. N.,Salaznikova,Rashchenko,Shamshina,Batrakov,Ivanov
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p. 769 - 777
(2019/02/26)
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- Gibbilimbol analogues as antiparasitic agents - Synthesis and biological activity against Trypanosoma cruzi and Leishmania (L.) infantum
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The essential oils from leaves of Piper malacophyllum (Piperaceae) showed to be mainly composed by two alkenylphenol derivatives: gibbilimbols A and B. After isolation and structural characterization by NMR and MS data analysis, both compounds were evaluated against promastigote/amastigote forms of Leishmania (L.) infantum as well as trypomastigote/amastigote forms of Trypanosoma cruzi. The obtained results indicated that gibbilimbol B displayed potential against the tested parasites and low toxicity to mammalian cells, stimulating the preparation of several quite simple synthetic analogues in order to improve its activity and to explore the preliminary structure-activity relationships (SAR) data. Among the prepared derivatives, compound LINS03003 (n-octyl-4-hydroxybenzylamine) displayed the most potent IC50 values of 5.5 and 1.8 μM against amastigotes of T. cruzi and L. (L.) infantum, respectively, indicating higher activity than the natural prototype. In addition, this compound showed remarkable selectivity index (SI) towards the intracellular forms of Leishmania (SI = 13.1) and T. cruzi (SI = 4.3). Therefore, this work indicated that preparation of synthetic compounds structurally based in the bioactive natural products could be an interesting source of novel and selective compounds against these protozoan parasites.
- Varela, Marina T.,Dias, Roberto Z.,Martins, Ligia F.,Ferreira, Daiane D.,Tempone, Andre G.,Ueno, Anderson K.,Lago, Jo?o Henrique G.,Fernandes, Jo?o Paulo S.
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p. 1180 - 1183
(2016/02/23)
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- Isouronium and N-hydroxyguanidinium derivatives as Cell growth inhibitors: A comparative study
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Based on the results obtained from a computational study on the suitability of the isouronium and N-hydroxyguanidinium cations as hydrogen bond donors/acceptors, the DNA binding of a series of isouronium derivatives was assessed by DNA thermal denaturation experiments and compared to related N-hydroxyguanidines. Due to the poor DNA binding observed, the nature of the diaromatic linker was explored by preparing the corresponding amide-linked bis-isouronium derivative and measuring its DNA affinity. Next, the inhibitory effects of the isouronium derivatives on cell viability were evaluated in two different cancer cell lines providing IC50 values in the range of 36.9-57.4 μM (HL-60, leukemia), and 17.3-33.9 μM (Kelly, neuroblastoma). These values are comparable to those previously found for the N-hydroxyguanidine series. Compounds with the -S- linker (3, 6, and 10) proved to be considerably active in the HL-60 cells and even more active in the Kelly cell line. No correlation was found between DNA minor groove binding and cell growth inhibition; hence, activity may depend on different modes of action. Further studies into the apoptotic potential of these compounds indicated that, besides inhibiting cell viability and proliferation, derivatives 9 and 10, are significant apoptosis-inducers in both cell lines. Results obtained with HL-60 cells suggest that G2/M arrest and subsequent apoptosis induced by compound 10 are associated with microtubular depolymerisation, loss of mitochondrial membrane potential and activation of the caspase cascade. Moreover, the effects of compound 10 on cell viability and apoptosis in two non-cancereous cell lines (NIH3T3 and MCF-10A) indicate none or minimal toxicity.
- Kahved?i?-Seljubac, Amila,Nathwani, Seema-Maria,Zisterer, Daniela M.,Rozas, Isabel
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p. 269 - 282
(2016/05/09)
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- Rh(III)-Catalyzed Redox-Neutral Annulation of Primary Benzamides with Diazo Compounds: Approach to Isoquinolinones
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Reported herein is a Rh-catalyzed redox-neutral annulation of primary benzamides with diazo compounds, representing an efficient and economic protocol to isoquinolinones. The procedure exhibited good functional group tolerability, scalability, and regioselectivity, obviating the need for oxidants, and only environmentally benign N2 and H2O were released. Further utilization of the method provided an alternative route to functionalized isoquinolines.
- Wu, Youzhi,Sun, Peng,Zhang, Kaifan,Yang, Tie,Yao, Hequan,Lin, Aijun
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p. 2166 - 2173
(2016/03/15)
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- Iodobenzene Dichloride in the Esterification and Amidation of Carboxylic Acids: In-Situ Synthesis of Ph3PCl2
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A novel, in-situ synthesis of dichlorotriphenylphosphorane (Ph3PCl2) is accomplished upon combining PPh3and the easily prepared hypervalent iodine reagent iodobenzene dichloride (PhICl2). The phosphorane is selectively generated in the presence of carboxylic acid or alcohol residues to rapidly produce acyl chlorides and alkyl chlorides in high yields. Addition of EtOH, PhOH, BnOH, Et2NH or CH2N2results in the direct synthesis of esters, amides and diazo ketones from carboxylic acids.
- Carle, Myriam S.,Shimokura, Grace K.,Murphy, Graham K.
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supporting information
p. 3930 - 3933
(2016/08/24)
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- A Facile and Efficient Synthesis of 4-Arylidene-2-phenyl-5(4H)-oxazolones and Their Antimicrobial Evaluation against Selected Human and Phytopathogens
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A simple and convenient method has been developed for the synthesis of a series of 2-(4-substituted phenyl)-4-(substituted arylidene)-1,3-oxazol-5-ones (5a–j) via reactions of hippuric acid with differently substituted aromatic aldehydes (4a–j) in sodium acetate, potassium acetate, calcium acetate, and ammonium acetate, respectively, which were tested for their efficiency as catalysts in both conventional and microwave-assisted synthetic methods in presence of 4 ? zeolites. The title compounds were evaluated for their antimicrobial properties against selected human pathogens (bacterial and fungal) and phytopathogens (fungal) and were compared with standard drugs. The results of the study are reported.
- Voosala, Christopher,Kilaru, Padma Suhasini,Dasari, Uday Kumar
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p. 909 - 916
(2016/11/23)
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- Synthesis of N -acyl- N, O -acetals mediated by titanium ethoxide
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N-Acyl-N,O-acetals are present in a number of bioactive natural products, and this unusual functional group can act as a synthetic precursor to unstable reactive N-acylimines. In this paper, a variety of N-acyl-O-ethyl-N,O-acetals was concisely prepared under mild conditions mediated by titanium ethoxide (Ti(OEt)4). The method also offers a new strategy to make other O-alkyl-N,O-acetals. Furthermore, this strategy was extended to the synthesis of an analogue of the natural product turtschamide.
- Li, Min,Luo, Bingling,Liu, Qi,Hu, Yumin,Ganesan,Huang, Peng,Wen, Shijun
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supporting information
p. 10 - 13
(2014/01/23)
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- Synthesis of some new glutamine linked 2,3-disubstituted quinazolinone derivatives as potent antimicrobial and antioxidant agents
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A series of novel glutamine linked 2,3-disubstituted quinazolinone conjugates was synthesized from methyl anthranilate and different substituted acids and acid chlorides. The compounds 5a-l were prepared in good yields. All compounds were screened for their antibacterial activity against Gram-positive and Gram-negative bacteria and for antifungal activity against Candida albicans and Aspergillus flavus using paper disk diffusion technique. The minimum inhibitory concentrations of the compounds were also determined by agar streak dilution method. The compound 5b was found to exhibit the most potent in vitro anti-microbial activity. When tested for their antioxidant activity, compounds 5i and 5l showed potent radical scavenging activity, while compound 5g had moderate effect against 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, nitric oxide, and superoxide radical scavenging assays. These results suggest that, the three quinazolinone analogs (5g, 5i, and 5l) could be considered as useful templates for future development to obtain more potent antioxidant agents.
- Prashanth,Revanasiddappa
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p. 2665 - 2676
(2013/07/26)
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- Synthesis and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold
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In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B-NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B-NS3 protease inhibitor with a 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor (1a24, IC50=3.4±0.2μM) of the WNV NS2B-NS3 protease. Molecular docking of 1a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.
- Samanta, Sanjay,Lim, Ting Liang,Lam, Yulin
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p. 994 - 1001
(2013/07/27)
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- POLYMERIZABLE COMPOUND, POLYMERIZABLE LIQUID CRYSTALLINE COMPOSITION, MACROMOLECULAR COMPOUND AND FILM
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A compound which has a benzoxazinone ring and an aromatic ring that directly bonds to the benzoxazinone ring, and has a mesogenic core substituted by a substituent having a polymerizable functional group is excellent in terms of durability, colorless, and exhibits a high Δn while having an azomethine bond.
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Paragraph 0114
(2014/01/07)
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- Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors
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Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
- Kümmerle, Arthur E.,Schmitt, Martine,Cardozo, Suzana V. S.,Lugnier, Claire,Villa, Pascal,Lopes, Alexandra B.,Romeiro, Nelilma C.,Justiniano, Hélène,Martins, Marco A.,Fraga, Carlos A. M.,Bourguignon, Jean-Jacques,Barreiro, Eliezer J.
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p. 7525 - 7545
(2012/11/06)
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- Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N-Thiomethylazetidinones
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The increasing emergence of multidrug-resistant microorganisms is one of the greatest challenges in the clinical management of infectious disease. New antimicrobial agents are therefore urgently required, particularly in the treatment of chronic and recurrent infections often associated with antibiotic-resistant pathogens, as in the case of cystic fibrosis (CF) patients. This study reports the antibacterial activity of a series of monocyclic β-lactams with an alkylidenecarboxyl chain or electron-withdrawing groups such as 4-OAc, 4-SAc, and 4-SO2Ph at the C4 position of the ring. N-Unsubstituted and N-thiomethyl derivatives were compared. A total of 33 azetidinones were tested for their activity against Gram-positive and Gram-negative bacterial clinical isolates. The combination of an N-thiomethyl group and a benzyl ester on the 4-alkylidene side chain were found to increase the potency against Gram-positive bacteria. The N-thiomethyl group clearly elevated the activity of 4-acetoxyazetidinones relative to the corresponding NH derivatives. The most active compounds showed minimum inhibitory concentration (MIC) values of 4 and 8mgL-1 against methicillin-resistant Staphylococcus aureus isolated from pediatric patients with CF.
- Galletti, Paola,Cocuzza, Clementina E. A.,Pori, Matteo,Quintavalla, Arianna,Musumeci, Rosario,Giacomini, Daria
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experimental part
p. 1919 - 1927
(2012/06/04)
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- A novel series of 2,5-disubstituted 1,3,4-thiadiazoles as potential anticonvulsant agent
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In pursuit for better antiepileptic drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-thiadiazoles as anticonvulsant pharmacophore, a series of novel N-({5-[(6-methyl-1-benzofuran-3-yl)methyl]-1,3,4-thiadiazol-2-yl}carbamothioyl)-2/3/4-substitutedbenzamide were designed, synthesized and evaluated for their anticonvulsant activity. The findings of the present studies confirmed that the pharmacophore model with four binding sites is crucial for anticonvulsant activity. Structure-activity relationships among synthesized compounds were also established.
- Rajak, Harish,Behera, Chinmay K.,Pawar, Rajesh S.,Singour, Pradeep K.,Kharya, Murli Dhar
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experimental part
p. 1149 - 1152
(2011/10/08)
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- First synthesis of antitubercular natural product 2-hydroxy-5-(4- hydroxybenzyl) benzaldehyde (forkienin)
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The synthesis of 2-hydroxy-5-(4-hydroxybenzyl)benzaldehyde an antitubercular compound, from the readily available starting compound p-hydroxybenzoic acid in 4 steps is described.
- Singh, Ashima,Sharma,Singh, Jasvinder
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experimental part
p. 148 - 149
(2009/04/07)
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- Direct arylation reactions catalyzed by Pd(OH)2/C: Evidence for a soluble palladium catalyst
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Palladium hydroxide on carbon (Pearlman's catalyst) effectively catalyzes direct arylation reactions of aryl iodides and bromides, providing excellent arylation-to-hydrodehalogenation ratios (>30:1) with broad scope for both intra- and intermolecular arylation processes. Studies aimed at determining the nature of the active catalyst indicate that an active homogeneous palladium species is produced under the reaction conditions.
- Parisien, Mathieu,Valette, Damien,Fagnou, Keith
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p. 7578 - 7584
(2007/10/03)
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- 1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of general formula (I) wherein D, E, R1, R2, R3, R4, R5, R6 and R7 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.
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Page/Page column 44
(2008/06/13)
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- Biphenyls as surrogates of the steroidal backbone. Part 2: Discovery of a novel family of non-steroidal 5-α-reductase inhibitors
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A new family of non-steroidal 5-α-reductase inhibitors was designed by replacing the steroid skeleton of an inhibitor related to estrone by a biphenyl moiety. This hypothesis originated from the reported estrogenic activity of a few biphenyl compounds (see Part 1 of this paper; Lesuisse et al. Bioorg. Med. Chem. Lett. 2001, 11, 1709). Two compounds turned out to be potent type 2 5-α-reductase inhibitors with IC50's of inhibition in the nanomolar range. These are to our knowledge amongst the most potent non-steroidal 5-α-reductase inhibitors described to date.
- Lesuisse, Dominique,Gourvest, Jean-Fran?ois,Albert, Eva,Doucet, Bernard,Hartmann, Catherine,Lefran?ois, Jean-Michel,Tessier, Sophie,Tric, Bernadette,Teutsch, Georges
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p. 1713 - 1716
(2007/10/03)
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- Efficient synthesis of resin-bound α-TMSdiazoketones and their use in solid-phase organic synthesis
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α-TMSdiazoketones on a solid support could be simply and efficiently prepared by reaction of the corresponding resin-bound acid chlorides with excess TMSdiazomethane, without any bases. These α-TMSdiazoketones were used via carbenes or carbenoids for a variety of solid-phase reactions. These useful solid-phase reactions allow efficient construction of diverse compound libraries by use of combinatorial chemistry, due to the high reactivity and wide applications of the carbenes or carbenoids. (C) 2000 Elsevier Science Ltd.
- Iso, Yasuyoshi,Shindo, Hirohisa,Hamana, Hiroshi
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p. 5353 - 5361
(2007/10/03)
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- Preparation process of acyl halide or sulfonyl halide
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A preparation process of acyl halide or sulfonyl halide which comprises reacting corresponding carboxylic acid or sulfonic acid with a haloiminium salt represented by the general formula (1): STR1 wherein R1 and R2 are same or different lower alkyl groups, X is a halogen atom, and n is an integer of 2 or 3.
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- Indenylacetic acid compounds
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4, 5, 6 or 7 Aryl substituted indenyl acetic acids and pharmaceutically acceptable salts, amides and esters thereof. The 4, 5, 6 or 7 aryl substituted indenyl acetic acids have anti-inflammatory, anti-pyretic and analgesic activity. The invention also includes methods for the preparation of these compounds, pharmaceutical compositions and methods of treating inflammation by administering these particular compounds to patients.
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