- Synthesis of novel thiazolothiazepine based HIV-1 integrase inhibitors.
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Thiazolothiazepines are among the smallest and most constrained inhibitors of human immunodeficiency virus type-1 integrase (HIV-1 IN) inhibitors (J. Med. Chem. 1999, 42, 3334). Previously, we identified two thiazolothiazepines lead IN inhibitors with antiviral activity in cell-based assays. Structural optimization of these molecules necessitated the design of easily synthesizable analogs. In order to design similar molecules with least number of substituent, herein we report the synthesis of 10 novel analogs. One of the new compounds (1) exhibited similar potency as the reference compounds, confirming that a thiazepinedione fused to a naphthalene ring system is the best combination for the molecule to accommodate into the IN active site. Thus, the replacement of sulfur in the thiazole ring with an oxygen does not seem considerably affect potency. On the other hand, the introduction of an extra methyl group at position 1 of the polycyclic system or the shift from a thiazepine to an oxazepine skeleton decreased potency. In order to understand their mode of interactions with IN active site, we docked all the compounds onto the previously reported X-ray crystal structure of IN. We observed that compounds 7-9 occupied an area close to D64 and Mg(2+) and surrounded by amino acid residues K159, K156, N155, E152, D116, H67, and T66. The oxygen atom of the oxazolo ring of 7 and 8 could chelate Mg(2+). These results indicate that the new analogs potentially interact with the highly conserved residues important for IN catalytic activities.
- Aiello, Francesca,Brizzi, Antonella,Garofalo, Antonio,Grande, Fedora,Ragno, Gaetano,Dayam, Raveendra,Neamati, Nouri
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- A convenient synthesis of new macrocyclic thioether-esters and ether-esters: Extraction properties of these esters for alkali, alkaline earth, and transition metal cations
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Macrocyclic thioether-esters and ether-esters have been prepared by treating 2,2′-dithiobenzoic acid dichloride and 1,2-benzendicarboxylic acid dichloride with appropriate glycols or dithiol. The complexing ability of these thioether-esters and ether-esters toward Li+, Na+, K+, Mg2+, Ca2+, Sr2+, Ba 2+, Co2+, and Ni2+ has been measured by the solvent extraction method. The extraction data indicate that compound 2 exhibits stronger selectivity toward Li+, 3 toward Ba2+, 4 toward K+, 5 toward Mg2+, 6 toward Ba2+ and Sr 2+, and 7 toward Co2+ and Ni2+ when compared with other cations. Copyright Taylor & Francis Inc.
- Seyedi, Seyed Mohammad,Shadkam,Ziafati
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Read Online
- Comparison of classic and microwave-assisted synthesis of benzo-thio crown ethers, and investigation of their ion pair extractions
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Macrocyclic benzo-thio crown ethers and benzo-oxo crown ethers were prepared using an esterification–ring closing method. These compounds were synthesised using 2,2′-dithiodibenzoyl chloride, and various glycols and dithiols, in the presence of pyridine base under a nitrogen atmosphere in chloroform. All reactions were performed under reflux condition with conventional heating and microwave (MW) irradiation. The synthesised macrocycles were characterised by FT-IR, 1H NMR, 13C NMR, LC-MS, and elemental analysis methods. Extraction studies have been performed on these original macrocycles using liquid-liquid ion-pair extraction with Li+, Na+, K+, Ni2+, Ca2+, Mg2+, Zn2+, Fe2+,Fe3+, Co3+, Pb2+, Cr3+, Ag+, and Cd2+.The KD, ext.%, ΔG and log KExt values were also calculated. While (U1-U7) ligands exhibits selectivity for Zn2+, Ag+, Ca2+, Pb2+, Fe3+, Cr3+, Co2+, Mg2+, Cd2+, and Ni2+ metal salts, they showed no selectivity for Li+, K+ and Na+ metal salts. Furthermore, Fe3+is the most selective cation for all ligands for competitive extraction. We also observed that microwave heating can have certain benefits over conventional ovens: reaction rate acceleration, milder reaction conditions, higher chemical yield, and lower energy usage. These ligands could be used as metal sensors, enzyme inhibitors, antimicrobial/antifungal agents, and in biological applications.
- Calisir, Umit,?i?ek, Baki
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Read Online
- Effective Laboratory-Scale Preparation of Axitinib by Two CuI-Catalyzed Coupling Reactions
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The discovery and development of an efficient synthesis route to axinitib is reported. The first-generation route researched by Pfizer implemented two Pd-catalyzed coupling reactions as key steps. In this work, the development of Heck-type and C-S coupling reactions catalyzed by CuI is briefly described, using an economial and practical protocol. Aspects of this route, such as selecting optimal ligands, solvent, and other conditions, are discussed in detail. The scale-up experiment was carried out to provide more than 300 g of active pharmaceutical ingredients of axitinib in Form XLI with 99.9% purity in 39% yield. In short, we provide a new choice of synthesis route to axitinib, through two copper-catalyzed coupling reactions with good yield.
- Zhai, Li-Hai,Guo, Li-Hong,Luo, Yang-Hui,Ling, Yang,Sun, Bai-Wang
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Read Online
- Axitinib intermediate compound and preparation method thereof
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The invention belongs to the field of pharmaceutical chemicals, and particularly relates to an axitinib intermediate compound and a preparation method thereof. The present invention provides a novel axitinib intermediate compound S-(2-(methylcarbamoyl) phenyl) dimethylthioformate, the invention also provides a preparation method thereof. The method comprises the following steps: dissolving 2-hydroxy-N-methylbenzamide in an organic solvent, and adding dimethylaminothioformyl chloride and a catalyst to obtain the S-(2-(methylcarbamoyl) phenyl) dimethylthioformate. The new intermediate compound can be used for preparing the axitinib important intermediate 2-sulfydryl-N-methylbenzamide, and the synthesis method provided by the invention is short in route, simple to operate and high in yield and purity of the obtained 2-sulfydryl-N-methylbenzamide, and is suitable for industrial production.
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Paragraph 0075-0076
(2021/01/24)
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- Synthesis, characterizations of aryl-substituted dithiodibenzothioate derivatives, and investigating their anti-Alzheimer's properties
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The main objective of the present study was to synthesize potential inhibitor/activators of AChE and hCA I-II enzymes, which are thought to be directly related to Alzheimer's disease. Dithiodibenzothioate compounds were synthesized by thioesterification. Six different thiolate compounds produced were characterized by 1H-, 13C-NMR, FT-IR, LC-MS/MS methods. HOMO-LUMO calculations and electronic properties of all synthesized compounds were comprehensively illuminated with a semi-empirical molecular orbital (SEMO) package for organic and inorganic systems using Austin Model 1 (AM1)-Hamiltonian as implemented in the VAMP module of Materials Studio. In addition, the inhibition effects of these compounds for AChE and hCA I-II in vitro conditions were investigated. It was revealed that TE-1, TE-2, TE-3, TE-4, TE-5, and TE-6 compounds inhibited the AChE under in vitro conditions. TE-1 compound activated the enzyme hCA I while TE-2, TE-3 TE-4 compounds inhibited it. TE-5 and TE-6, on the other hand, did not exhibit a regular inhibition profile. Similarly, TE-1 activated the hCA II enzyme whereas TE-2, TE-3, TE-4, and TE-5 compounds inhibited it. TE-6 compound did not have a consistent inhibition profile for hCA II. Docking studies were performed with the compounds against AChE and hCA I-II receptors using induced-fit docking method. Molecular Dynamics (MD) simulations for best effective three protein-ligand couple were conducted to explore the binding affinity of the considered compounds in semi-real in-silico conditions. Along with the MD results, TE-1-based protein complexes were found more stable than TE-5. Based on these studies, TE-1 compound could be considered as a potential drug candidate for AD. Communicated by Ramaswamy H. Sarma.
- ?al???r, ümit,?i?ek, Baki,Adem, ?evki,Akkemik, Ebru,Camadan, Yasemin,Eyüpo?lu, Volkan
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- Preparation method of dithiobenzamide compound
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The invention provides a preparation method of a dithiobenzamide compound, and relates to the technical field of organic synthesis. The method disclosed by the invention has the advantages that applicable substrates are richer, and the method can be used for synthesizing various dithiodibenzoyl compounds; reaction conditions are mild, the synthesis reaction process is simple to operate, and practicability is achieved; the post-treatment operation is simple and convenient, and the product yield and purity are high; and the reaction process is green and environment-friendly, and the preparationmethod meets the requirements of large-scale industrial production.
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Paragraph 0061-0065
(2020/08/02)
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- Synthetic method 1-2 - benzisothiazol -3 -one compound (by machine translation)
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The invention discloses a synthetic method of 1-2 - benzisothiazol -3 -one compound, and belongs to the field of chemical synthesis. 2 - 1-benzisothiazol 2 -one compounds are synthesized through acid chlorination, amidation and cyclization reaction by using the sulfenyl-substituted benzoic acid extracted from BIT process -3 - waste water as a starting raw material. The method disclosed by the invention has the advantages of mild reaction conditions, simple and convenient operation, strong practicability, less waste water, high product purity and the like, and is suitable for large-scale industrial production. The technical scheme provided by the invention is resource utilization and preparation 1 of wastewater extract produced in BIT production, and a feasible method is provided for the 2 -benzisothiazol -3 -one compound. (by machine translation)
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Paragraph 0074-0076
(2020/09/09)
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- Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines
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We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed us to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in the mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors.
- Castelli, Riccardo,Scalvini, Laura,Vacondio, Federica,Lodola, Alessio,Anselmi, Mattia,Vezzosi, Stefano,Carmi, Caterina,Bassi, Michele,Ferlenghi, Francesca,Rivara, Silvia,M?ller, Ingvar R.,Rand, Kasper D.,Daglian, Jennifer,Wei, Don,Dotsey, Emmanuel Y.,Ahmed, Faizy,Jung, Kwang-Mook,Stella, Nephi,Singh, Simar,Mor, Marco,Piomelli, Daniele
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p. 1261 - 1280
(2019/12/25)
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- Bioisosteric investigation of ebselen: Synthesis and in vitro characterization of 1,2-benzisothiazol-3(2H)-one derivatives as potent New Delhi metallo-β-lactamase inhibitors
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Carbapenem-resistant Enterobacteriaceae (CRE) producing New Delhi metallo-β-lactamase (NDM-1) cause untreatable bacterial infections, posing a significant threat to human health. In the present study, by employing the concept of bioisosteric replacement of the selenium moiety of ebselen, we have designed, synthesized and characterized a small compound library of 2-substituted 1,2-benzisothiazol-3(2H)-one derivatives and related compounds for evaluating their cytotoxicity and synergistic activity in combination with meropenem against the E. coli Tg1 (NDM-1) strain. The most promising compound 3a demonstrated potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE strains with FICI as low as 0.09. Moreover, its IC50 value and inhibition mechanism were also confirmed by using the enzyme inhibition assay and the ESI-MS analysis respectively. Importantly, compound 3a has acceptable toxicity and is not a PAINS. Because of its structural simplicity and potent synergistic activity in combination with meropenem, we propose that compound 3a may be a promising meropenem adjuvant and a new series of such compounds may worth further investigations.
- Jin, Wen Bin,Xu, Chen,Cheung, Qipeng,Gao, Wei,Zeng, Ping,Liu, Jun,Chan, Edward W.C.,Leung, Yun-Chung,Chan, Tak Hang,Wong, Kwok-Yin,Chen, Sheng,Chan, Kin-Fai
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- Silane, rubber mixture containing the silane and vehicle tyre having the rubber mixture in at least one component
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The invention relates to a silane, to a rubber mixture comprising the silane and to a vehicle tire comprising the rubber mixture in at least one component. The inventive silane has the following formula I) [in-line-formulae](R1)oSi—R2—X-A-Y-[A-Y-]m-A-Sk-A-[-Y-A]mY-A-X—R2—Si(R1)o,[/in-line-formulae] wherein, according to the invention, the silane has spacer groups between the respective silyl groups and the Sk moiety which have at least two aromatic groups A and the linking units X and Y, wherein the groups X within a molecule may be identical or different from each other and are selected from the groups —HNC(═O)—, —C(═O)NH—, —C(═O)O—, —OC(═O)—, —OC(═O)NH—, —HNC(═O)O—, —R3NC(═O)NR3—, —R3NC(═NR3)NR3—, —R3NC(═S)NR3—, wherein at least one R3 within each group X is a hydrogen atom; and wherein the groups Y within a molecule may be identical or different from each other and are selected from the groups —HNC(═O)—, —C(═O)NH—, —C(═O)O—, —OC(═O)—, —OC(═O)NH—,—HNC(═O)O—, —R4NC(═O)NR4—, —R4NC(═NR4)NR4—, —R4NC(═S)NR4—, wherein at least one R4 within each group Y is a hydrogen atom. The inventive rubber mixture comprises at least one inventive silane.
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Page/Page column 17-18
(2020/12/21)
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- Ebsulfur as a potent scaffold for inhibition and labelling of New Delhi metallo-β-lactamase-1 in vitro and in vivo
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The superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has grown into an emerging threat, labelling and inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. Here, we report a potent covalent scaffold, ebsulfur, for targeting the protein in vitro and in vivo. Enzymatic kinetic study indicated that eighteen ebsulfurs gained except 1a–b and 1f inhibited NDM-1, exhibiting an IC50 value ranging of 0.16–9 μM, and 1g was found to be the best, dose- and time-dependent inhibitor with an IC50 of 0.16 μM. Also, these ebsulfurs effectively restored the antibacterial activity of cefazolin against E. coli expressing NDM-1, and the best effect was observed to be from 1g, 1i and 1n, resulting in an 256-fold reduction in MIC of the antibiotic at a dose of 16 μg/mL. The equilibrium dialysis study implied that the ebsulfur disrupted the coordination of one Zn(II) ion at active site of NDM-1. Labelling of NDM-1 using a constructed fluorescent ebsulfur Ebs-R suggested that the inhibitor covalently bound to the target through SDS-PAGE analysis in vitro. Also, labelling NDM-1 in living E. coli cells with Ebs-R by confocal microscopic imaging showed the real-time distribution change process of intracellular recombinant protein NDM-1. Moreover, the cytotoxicity of these ebsulfurs against L929 mouse fibroblastic cells was tested, and their capability to restore antibacterial activity of antibiotic against clinical strains E. coli EC08 producing NDM-1 was determined. The ebsulfur scaffold proposed here is valuable for development of the covalent irreversible inhibitors of NDM-1, and also for labelling the target in vitro and in vivo.
- Su, Jianpeng,Liu, Jiayun,Chen, Cheng,Zhang, Yuejuan,Yang, Kewu
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supporting information
p. 192 - 201
(2018/12/02)
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- Synthesis of diaryl sulfides through C–H bond functionalization of arylamides with cobalt salt and elemental sulfur
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A cobalt(II)-mediated, highly chemoselective thioarylation reaction of arylamides with elemental sulfur was reported. This reaction led to the formation of various symmetric diaryl sulfides in yields of up to 65% under mild reaction conditions. A cobalt-sulfur radical process was proposed based on preliminary results and mechanistic studies.
- Li, Jian-Ye,Huang, Jun,Zhang, Shi-Jin,Yao, Chunna,Sun, Wen-Wu,Liu, Bin,Zhou, Yingbi,Wu, Bin
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supporting information
p. 895 - 899
(2019/02/26)
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- Electron paramagnetic resonance spectroscopy as a probe of hydrogen bonding in heme-Thiolate proteins
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Despite utilizing a common cofactor binding motif, hemoproteins bearing a cysteine-derived thiolate ligand (heme-Thiolate proteins) are involved in a diverse array of biological processes ranging from drug metabolism to transcriptional regulation. Though the origin of heme-Thiolate functional divergence is not well understood, growing evidence suggests that the hydrogen bonding (H-bonding) environment surrounding the Fe-coordinating thiolate influences protein function. Outside of X-ray crystallography, few methods exist to characterize these critical H-bonding interactions. Electron paramagnetic resonance (EPR) spectra of heme-Thiolate proteins bearing a six-coordinate, Fe(III) heme exhibit uniquely narrow low-spin (S = 1/2), rhombic signals, which are sensitive to changes in the heme-Thiolate H-bonding environment. To establish a well-defined relationship between the magnitude of g-value dispersion in this unique EPR signal and the strength of the heme-Thiolate H-bonding environment, we synthesized and characterized of a series of six-coordinate, aryl-Thiolate-ligated Fe(III) porphyrin complexes bearing a tunable intramolecular H-bond. Spectroscopic investigation of these complexes revealed a direct correlation between H-bond strength and g-value dispersion in the rhombic EPR signal. Using density functional theory (DFT), we elucidated the electronic origins of the narrow, rhombic EPR signal in heme-Thiolates, which arises from an Fe-S pI-dI bonding interaction. Computational analysis of the intramolecularly H-bonded heme-Thiolate models revealed that H-bond donation to the coordinating thiolate reduces thiolate donor strength and weakens this Fe-S interaction, giving rise to larger g-value dispersion. By defining the relationship between heme-Thiolate electronic structure and rhombic EPR signal, it is possible to compare thiolate donor strengths among heme-Thiolate proteins through analysis of low-spin, Fe(III) EPR spectra. Thus, this study establishes EPR spectroscopy as a valuable tool for exploring how second coordination sphere effects influence heme-Thiolate protein function.
- Dent, Matthew R.,Milbauer, Michael W.,Hunt, Andrew P.,Aristov, Michael M.,Guzei, Ilia A.,Lehnert, Nicolai,Burstyn, Judith N.
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p. 16011 - 16027
(2019/11/28)
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- Preparation methods of acyl chloride and thioxanthone
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The present invention relates to the field of fine chemicals and pharmaceutical chemicals, particularly to new economical preparation process technologies of ortho-chlorosulfenyl aroyl chloride and thioxanthone compounds, and applications of the thioxanthone compounds in synthesis of photoinitiators or other new material chemicals.
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Paragraph 0015
(2018/04/01)
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- ALKYNYL INDAZOLE DERIVATIVE AND USE THEREOF
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The main object of the present invention is to provide a novel compound which has a VEGF receptor tyrosine kinase inhibitory activity and is useful as an active ingredient for the treatment of diseases accompanying angiogenesis or edema, for example, age-related macular degeneration or the like. The present invention includes, for example, an alkynyl indazole derivative represented by the following general formula (I), a pharmaceutical acceptable salt thereof, and a medicine containing thereof.
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Paragraph 0244; 0245
(2017/02/24)
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- Broad spectrum anti-infective properties of benzisothiazolones and the parallels in their anti-bacterial and anti-fungal effects
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Various mono- and bis-benzisothiazolone derivatives were synthesized and screened against different strains of bacteria and fungi in order to understand the effect of multiple electrophilic sulfur atoms and substitution pattern in the immediate vicinity of reactive sulfur. Staphyllococcus aureus-ATCC 7000699, MRSA and S. aureus-ATCC 29213 (Quality Control strain) were more susceptible to this class of compounds, and the most potent derivative 1.15 had MIC50 of 0.4?μg/mL (cf. Gentamicin?=?0.78?μg/mL). CLogP value, optimally in the range of 2.5–3.5, appeared to contribute more to the activity than the steric and electronic effects of groups attached at nitrogen. By and large, their anti-fungal activities also followed a similar trend with respect to the structure and CLogP values. The best potency of IC50?=?0.1?μg/mL was shown by N-benzyl derivative (1.7) against Aspergillus fumigatus; it was also potent against Candida albicans, Cryptococcus neoformans, Sporothrix schenckii, and Candida parapsilosis with IC50 values ranging from 0.4 to 1.3?μg/mL. Preliminary studies also showed that this class of compounds have the ability to target malaria parasite with IC50 values in low micromolar range, and improvement of selectivity is possible through structure optimization.
- Gopinath,Yadav,Shukla,Srivastava,Puri,Muraleedharan
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supporting information
p. 1291 - 1295
(2017/06/19)
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- A flower-lush type compound and use thereof
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The invention relates to a fluorescent probe for detecting superoxide anions (O2-) and sulfane sulfur, in particular to a cyanine compound and application thereof. The cyanine compound is as shown in general formula I and serves as the fluorescent probe for hydrogen sulfide. In the presence of the superoxide anions (O2-) and sulfane sulfur, the corresponding fluorescence-emission wavelength and strength of the fluorescent probe vary, and the fluorescent probe can be used for detecting the superoxide anions (O2-) and sulfane sulfur, can greatly reduce the interference of external detection conditions and is high in detection signal-to-noise ratio and good in sensitivity and selectivity. The compound serving as the fluorescent probe can be used for linkage detection of the level of the superoxide anions (O2-) and sulfane sulfur in complex biological samples and is of great biomedicine significance for studying cellular signal transduction of the superoxide anions (O2-) and sulfane sulfur. Formula I.
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Paragraph 0050; 0052; 0053
(2017/10/07)
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- Development of ebsulfur analogues as potent antibacterials against methicillin-resistant Staphylococcus aureus
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Antibiotic resistance is a worldwide problem that needs to be addressed. Staphylococcus aureus is one of the dangerous “ESKAPE” pathogens that rapidly evolve and evade many current FDA-approved antibiotics. Thus, there is an urgent need for new anti-MRSA compounds. Ebselen (also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one) has shown promising activity in clinical trials for cerebral ischemia, bipolar disorder, and noise-induced hearing loss. Recently, there has been a renewed interest in exploring the antibacterial properties of ebselen. In this study, we synthesized an ebselen-inspired library of 33 compounds where the selenium atom has been replaced by sulfur (ebsulfur derivatives) and evaluated them against a panel of drug-sensitive and drug-resistant S. aureus and non-S. aureus strains. Within our library, we identified three outstanding analogues with potent activity against all S. aureus strains tested (MIC values mostly ?2?μg/mL), and numerous additional ones with overall very good to good antibacterial activity (1–7.8?μg/mL). We also characterized the time-kill analysis, anti-biofilm ability, hemolytic activity, mammalian cytotoxicity, membrane-disruption ability, and reactive oxygen species (ROS) production of some of these analogues.
- Ngo, Huy X.,Shrestha, Sanjib K.,Green, Keith D.,Garneau-Tsodikova, Sylvie
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supporting information
p. S1 - S53
(2016/12/07)
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- Benzoisothiazolone organo/copper-cocatalyzed redox dehydrative construction of amides and peptides from carboxylic acids using (EtO)3P as the reductant and O2 in air as the terminal oxidant
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Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5-36 h at 50 °C using catalytic quantities of a redox-active benzoisothiazolone and a copper complex. These catalytic "oxidation-reduction condensation" reactions are carried out open to dry air using O2 as the terminal oxidant and a slight excess of triethyl phosphite as the reductant. Triethyl phosphate is the easily removed byproduct. These simple-to-run catalytic reactions provide practical and economical procedures for the acylative construction of C-N bonds.
- Liebeskind, Lanny S.,Gangireddy, Pavankumar,Lindale, Matthew G.
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supporting information
p. 6715 - 6718
(2016/06/14)
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- A novel kind of dimmer (excimer)-induced-AIE compound 2- phenylisothiazolo[5,4-b]pyridin-3(2H)-one as high selective bisulfite anion probe
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An interesting dimmer (excimer)-induced-AIE characteristic of 2-phenylisothiazolo[5,4-b]pyridin-3(2H)-one was observed. By using a ring-opening reaction, we developed a novel fluorescent probe based on sub-micron particles of 2-phenylisothiazolo[5,4-b]pyridin-3(2H)-one in water.
- Yang, Bingchuan,Niu, Xiaoyi,Huang, Zixiao,Zhao, Cuihua,Liu, Yang,Ma, Chen
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supporting information
p. 8250 - 8254
(2013/09/02)
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- Benzisothiazolones arrest the cell cycle at the G2/M phase and induce apoptosis in HeLa cells
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Anticancer activities of a series of benzisothiazolones having alkyl, aryl and aralkyl substituents on the nitrogen atom and the mechanistic basis of cytotoxicity are presented. Cellular responses like DNA laddering, disruption of mitochondrial membrane potential and caspase-3 activation on incubation of HeLa cells with representative compounds from this group suggested the induction of apoptosis through an intrinsic pathway. Their ability to arrest the cell cycle at the G2/M phase was confirmed by flow cytometric analysis.
- Gopinath, Pushparathinam,Ramalingam, Krishnan,Muraleedharan, Kannoth Manheri,Karunagaran, Devarajan
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p. 749 - 752
(2013/06/04)
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- Oxidative folding of lysozyme with aromatic dithiols, and aliphatic and aromatic monothiols
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In vitro protein folding of disulfide containing proteins is aided by the addition of a redox buffer, which is composed of a small molecule disulfide and/or a small molecule thiol. In this study, we examined redox buffers containing asymmetric dithiols 1-5, which possess an aromatic and aliphatic thiol, and symmetric dithiols 6 and 7, which possess two aromatic thiols, for their ability to fold reduced lysozyme at pH 7.0 and 8.0. Most in vivo protein folding catalysts are dithiols. When compared to glutathione and glutathione disulfide, the standard redox buffer, dithiols 1-5 improved the protein folding rates but not the yields. However, dithiols 6 and 7, and the corresponding monothiol 8 increased the folding rates 8-17 times and improved the yields 15-42% at 1 mg/mL lysozyme. Moreover, aromatic dithiol 6 increased the in vitro folding yield as compared to the corresponding aromatic monothiol 8. Therefore, aromatic dithiols should be useful for protein folding, especially at high protein concentrations.
- Patel, Amar S.,Lees, Watson J.
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experimental part
p. 1020 - 1028
(2012/03/10)
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- Crucial role of selenium in the virucidal activity of benzisoselenazol- 3(2h)-ones and related diselenides
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Various N-substituted benzisoselenazol-3(2H)-ones and their non-seleniumcontaining analogues have been synthesized and tested against selected viruses (HHV-1, EMCV and VSV) to determine the extent to which selenium plays a role in antiviral activity. The data presented here show that the presence of selenium is crucial for the antiviral properties of benzisoselenazol-3(2H)-ones since their isostructural analogues having different groups but lacking selenium either did not show any antiviral activity or their activity was substantially lower. The open-chain analogues of benzisoselenazol- 3(2H)-ones-diselenides also exhibited high antiviral activity while selenides and disulfides were completely inactive towards model viruses.
- Pietka-Ottlik, Magdalena,Potaczek, Piotr,Piasecki, Egbert,Mlochowski, Jacek
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scheme or table
p. 8214 - 8228
(2011/03/19)
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- Synthesis of new multibenzo oxygen-sulfur donor macrocycles containing lactams at room temperature
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Some new oxygen-sulfur, multibenzo macrocyclic ligands containing amide groups have been prepared using the macrocyclization process with the reaction of 2,2'-thiobis-[4-methyl(2-aminophenoxy)phenyl ether] as a symmetrical diamine with appropriate dicarboxylicacid dichlorides in moderate yields. This macrocyclization led to the formation of di- and tetramide macrocycles. These reactions were routinely carried out at ambient temperature in CH2Cl2 as solvent in high dilution without template effect conditions. It is found that sulfur the atom affects the rigidity of the macrocycles and diastereotopicity of nuclei in the ring of these series of macrocyclic compounds.
- Shockravi, Abbas,Sadeghpour, Mahdieh,Zakeri, Masoomeh,Abouzari-Lotf, Ebrahim,Olyaei, Abolfazl
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experimental part
p. 808 - 815
(2010/07/08)
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- Cu and Ag catalyzed oxidative arylthiation of terminal acetylenes
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A mild Cu or Ag catalyzed oxidative arylthiation of terminal acetylenes is introduced. The process, featuring metal catalyzed C-H bond activation as a key step, leads to the formation of highly substituted mercaptoacetylenes under unprecedented neutral conditions.
- Henke, Adam,Srogl, Jiri
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supporting information; experimental part
p. 6819 - 6821
(2010/10/20)
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- VEGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to VEGFR inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 54
(2009/04/25)
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- Design, syntheses, and characterization of dioxo-molybdenum(vi) complexes with thiolate ligands: Effects of intraligand NH...S hydrogen bonding
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Presence of the hydrogen bonding near a metal center can influence the properties of the complex. Here, we describe changes in redox and spectral properties in discrete dioxo-molybdenum centers coordinated by a single thiolato ligand that can support an intra-ligand hydrogen bond. We have utilized thiophenolato ligands that can harbor hydrogen bonding between the thiophenolato sulfur with an amide functionality creating either a five- or a six-membered ring. Methylation of the amide functionality removes the NH...S hydrogen bonding thus providing a basis for understanding the effect of hydrogen bonding. These thiophenolato ligands have been used in synthesizing dioxo-MoVI complexes of type Tp*MoO2(S-o-RC6H4), where R = CONHMe (11), CONMe2 (12), NHCOMe (13), and N(Me)COMe (14). The complexes have been characterized by NMR, infrared, and UV-visible spectroscopy. Spectroscopic data clearly indicate the presence of hydrogen bonding in both 11 and 13, and stronger in 13, where hydrogen bonding stabilizes a five-membered ring. All complexes exhibit a MoVI/MoV redox couple and redox potentials are modulated by the nature of H-bonding. Compound 14 with the electron-releasing N(Me)COMe group has the highest reduction potential and is more difficult to reduce. The Royal Society of Chemistry.
- Sengar, Raghvendra S.,Miller, Jonathan J.,Basu, Partha
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p. 2569 - 2577
(2008/09/20)
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- Polymer-filler coupling additives
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Polymer-filler coupling compounds with the formula B-A-Sx-N are claimed. In these compounds, B is an azaheterocyclic oxygen or sulfur containing moiety, or an allyltin moiety; Sx is a polysulfide, where x is between 2 and about 10; A is a linking atom or group that forms a bridge between B and Sx; and N is a blocking group. Sx can be a disulfide. N can be a conventional blocking group or other group such as -A-B. Methods for using the polymer-filler coupling compounds to modify polymers containing unsaturated carbon-carbon bonds and promote filler dispersion are also claimed. Additionally, vulcanizable rubber compositions containing the polymer-filler coupling compounds and methods for making vulcanized rubber compositions using the polymer-filler coupling compounds are also claimed.
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Page/Page column 14
(2008/06/13)
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- SULPHONIUM SALT INITIATORS
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Compounds of the formula (I), (II), (III), (IV) and wherein, R is hydrogen, C1-C20alkyl; C2-C20alkyl interrupted by one or more O; is -L-X-R2 or - L-R2; R1 has ofr example one of the meanings as given for R; R2 is a monovalent sensitizer or photoinitiator moiety; Ar1 and Ar2 for example independently of one another are phenyl substituted by C1-C20alkyl, halogen or OR3; or are unsubstituted naphthyl, anthryl, phenanthryl or biphenylyl; or are naphthyl, anthryl, phenanthryl or biphenylyl substituted by C1-C20alkyl, OH or OR3; or are -Ar4-A-Ar3; Ar3 is unsubstituted phenyl naphthyl, anthryl, phenanthryl or biphenylyl; or is phenyl, naphthyl, anthryl, phenanthryl or biphenylyl substituted by C1-C20alkyl, OR3 or benzoyl; Ar4 is phenylene, naphthylene, anthrylene or phenanthrylene; A is a direct bond, S, O or C1-C20alkylene; X is CO, C(O)O, OC(O), O, S or NR3 ; L is C1-C20alkylene or C2-C20alkylene interrupted by one or more O; R3 is C1-C20alkyl or C1-C20hydroxyalkyl; and Y is an anion, are suitable as photolatent acid generators.
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Page/Page column 69; 11
(2008/06/13)
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- METHODS FOR PREPARING INDAZOLE COMPOUNDS
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The invention relates to methods for preparing indalzole compounds having formula (I) or pharmaceutically acceptable salts or solvates thereof. Compounds of the formula (I) are useful as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cellular proliferation mediated by protein kinases.
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Page/Page column 27
(2008/06/13)
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- Proton-and redox-controlled switching of photo-and electrochemiluminescence in thiophenyl-substituted boron-dipyrromethene dyes
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A luminescent molecular switch in which the active thiol/disulfide switching element is attached to a meso-phenyl-substituted boron-dipyr-romethene (BDP) chromophore as the signalling unit is presented. The combination of these two functional units offers great versatility for multimodal switching of luminescence: 1)deprotonation/protonation of the thiol/thiolate moiety allows the highly fluorescent meso-p-thiophenol-BDP and its non-fluorescent thiolate analogue to be chemically and reversibly interconverted, 2) electrochemical oxidation of the monomeric dyes yields the fluorescent disulfide-bridged bichromophoric dimer, also in a fully reversible process, and 3) besides conventional photoexcitation, the well separated redox potentials of the BDP also allow the excited BDP state to be generated electro-chemically (i.e., processes 1) and 2) can be employed to control both photo-and electrochemiluminescence (ECL) of the BDP). The paper introduces and characterizes the various states of the switch and discusses the underlying mechanisms. Investigation of the ortho analogue of the dimer provided insight into potential chromophore-chromophore interactions in such bichromophoric architectures in both the ground and the excited state. Comparison of the optical and redox properties of the two disulfide dimers further revealed structural requirements both for redox switches and for ECL-active molecular ensembles. By employing thiol/disulfide switching chemistry and BDP luminescence features, it was possible to create a prototype molecular ensemble that shows both fully reversible proton-and redox-gated electrochemiluminescence.
- Roehr, Holger,Trieflinger, Christian,Rurack, Knut,Daub, Joerg
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p. 689 - 700
(2007/10/03)
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- 2-(1H-INDOLYLSULFANYL)-BENZYL AMINE DERIVATIVES AS SSRI
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The present invention relates to aniline derivatives of the general formula I and their use as serotonin reuptake inhibitors and preferably also norepinephrine reuptake inhibitors in the treatment of depression, anxiety, affective disorders, pain disorders, attention deficit hyperactivity disorder (ADHD) and stress urinary incontinence.
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Page/Page column 70-71
(2008/06/13)
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- NOVEL 1,4-BENZOTHIAZEPANS AND DERIVATIVES THEREOF
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The invention relates to novel compounds of 1,4-benzothiazepans and 1,4-benzothiazepins, especially of 5-one compounds, and to the use of the same as medicaments.
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Page/Page column 13
(2010/02/13)
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- Synthesis and anti-HIV activity of metal complexes of SRR-SB3
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The disulphide diamide SRR-SB3 (7-methyl-6,7,8,9-tetrahydrodibenzo [c,k] [1,2,6,9] dithiadiazacyclododecine-5-10-dione) and its metal complexes have been synthesized and characterised by elemental analyses, IR, 1H{ 13C} NMR, mass spectra and magnetic moment data. The complexation of the ligand SRR-SB3 with several metal ions such as ruthenium(III), cobalt(II), iron(III), lead(II), copper(II), nickel(II), zinc(II), manganese(II) and palladium(II) chloride have been studied. The metal ions, Ru and Zn are found to complex successfully with SRR-SB3. The metal complexes have been found to inhibit the replication of HIV-1 (IIIB) and HIV-2 (ROD) strains using MT-4 cells with a selectivity index ranging from 5 to 27.
- Bhowon, Minu G.,Laulloo, B. S. Jhaumeer
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p. 1131 - 1133
(2007/10/03)
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- The design and synthesis of redox core-alpha amino acid composites based on thiol-disulfide exchange mechanism and a comparative study of their zinc abstraction potential from [CCXX] boxes in proteins
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The design and synthesis of agents that can abstract zinc from their [CCXX] (C=cysteine; X=cysteine/histidine) boxes by thiol-disulfide exchange-having as control, the redox parities of the core sulfur ligands of the reagent and the enzyme, has been illustrated, and their efficiency demonstrated by monitoring the inhibition of the transcription of calf thymus DNA by E. coli RNA polymerase, which harbors two zinc atoms in their [CCXX] boxes of which one is exchangeable. Maximum inhibition possible with removal of the exchangeable zinc was seen with redox-sulfanilamide-glutamate composite. In sharp contrast, normal chelating agents (EDTA, phenanthroline) even in a thousand fold excess showed only marginal inhibition, thus supporting an exchange mechanism for the metal removal.
- Ranganathan, Subramania,Muraleedharan,Bharadwaj, Parimal,Chatterji, Dipankar,Karle, Isabella
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p. 2861 - 2874
(2007/10/03)
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- Synthesis and biological properties of amino acid amide ligand-based pyridinioalkanoyl thioesters as anti-HIV agents
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Hyper-mutable retroviruses such as HIV can become rapidly resistant to drugs used to treat infection. Strategies for coping with drug-resistant strains of virus include combination therapies, using viral protease and reverse transcriptase inhibitors. Another approach is the development of antiviral agents that attack mutationally nonpermissive targets that have functions essential for viral replication. Thus, the highly conserved nucleocapsid protein, NCp7, was chosen as a prime target in our search for novel anti-HIV agents that can overcome the problem of viral drug resistance. Recently, we reported (J. Med. Chem. 1999, 42, 67) a novel chemotype, the pyridinioalkanoyl thioesters (PATEs), based on 2-mercaptobenzamides as the thiol component and having its amide nitrogen substituted with various phenylsulfonyl moieties. These compounds were identified as relatively nontoxic anti-HIV agents in the XTT cytoprotection assay. In this study, we wish to report a separate genre of active PATEs wherein the thiol component consists of an N-2-mercaptobenzoyl-amino acid derivative. Active derivatives (EC50 10 μM) reported herein were confined to amino acid primary amides or methyl amides having side chains no larger than isobutyl. Amino acids terminating in free carboxyl or carboxylic acid ester groups were mostly inactive. Selected compounds were shown to be active on chronically infected CEM/SK-1, TNFα-induced U1, ACH-2 cells and virucidal on cell-free virus, latently infected U1 cells and acutely infected primary peripheral blood mononuclear cells (PBMCs).
- Song, Yongsheng,Goel, Atul,Basrur, Venkatesha,Roberts, Paula E.A,Mikovits, Judy A,Inman, John K,Turpin, Jim A,Rice, William G,Appella, Ettore
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p. 1263 - 1273
(2007/10/03)
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- Metal-dependent inhibition of HIV-1 integrase
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Human immunodeficiency virus type 1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Therefore, IN inhibitors are being sought for chemotherapy against AIDS. We had previously identified a series of salicylhydrazides as potent inhibitors of IN in vitro (Neamati, N.; et al. J. Med. Chem. 1998, 41, 3202-3209.). Herein, we report the design, synthesis, and antiviral activity of three novel mercaptosalicylhydrazide (MSH) derivatives. MSHs were effective against the IN catalytic core domain and inhibited IN binding to HIV LTR DNA. They also inhibited catalytic activities of IN in IN-DNA preassembled complexes. Site-directed mutagenesis and molecular modeling studies suggest that MSHs bind to cysteine 65 and chelate Mg2+ at the active site of HIV-1 IN. Contrary to salicylhydrazides, the MSHs are 300-fold less cytotoxic and exhibit antiviral activity. They are also active in Mg2+-based assays, while IN inhibition by salicylhydrazides is strictly Mn2+-dependent. Additionally, in target and cell-based assays, the MSHs have no detectable effect on other retroviral targets, including reverse transcriptase, protease, and virus attachment, and exhibit no detectable activity against human topoisomerases I and II at concentrations that effectively inhibit IN. These data suggest that MSHs are selective inhibitors of HIV-1 IN and may serve as leads for antiviral therapeutics.
- Neamati, Nouri,Lin, Zhaiwei,Karki, Rajeshri G.,Orr, Ann,Cowansage, Kiriana,Strumberg, Dirk,Pais, Godwin C. G.,Voigt, Johannes H.,Nicklaus, Marc C.,Winslow, Heather E.,Zhao, He,Turpin, Jim A.,Yi, Jizu,Skalka, Anna Marie,Burke Jr., Terrence R.,Pommier, Yves
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p. 5661 - 5670
(2007/10/03)
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- Structure and mechanism of hydrolysis of diaryl(acylamino)(chloro)-λ4-sulfanes and diaryl(acylamino)sulfonium salts
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Aryl (methylaminocarbonylaryl) sulfides were converted by t-BuOCl to diaryl(acylamino)(chloro)-λ4-sulfanes or the corresponding diaryl(acylamino)sulfonium chlorides depending on the substituent of the S-aryl group. 1H NMR data showed that chloro-λ4-sulfanes exist only in CDCl3 and DMSO-d6 solvents, whereas in CD3OD complete ionic dissociation takes place, leading to sulfonium chlorides. Both the chemical shifts of 1H NMR signals and NOE data suggest that chloro-λ4-sulfanes and sulfonium salts having an o-MeO, o-Cl or o-Me substituent on the phenyl ring assume a skew conformation, whereas the aryl ring in compounds without an ortho-substituent can rotate practically free about the S-C(1') axis. In o-MeO-substituted derivatives there exists an equatorial 1,4 type S...O close contact. Sulfonium salts with axial 1,5 type S...O close contacts involving neighbouring COOMe, CONHMe, COMe or NO2 groups occur in butterfly conformation, like spiro-λ4-sulfanes. There is a correlation between the 15N chemical shift of the amide-nitrogen and the elongation of the S-N covalent bond, by which the interdepending S-N, S-Cl and S...O bonds can be characterized. Effective intermolecular S...O interaction was detected between the sulfonium centre and solvent molecules having a negatively polarized oxygen atom. The hydrolysis of sulfonium salts yielding sulfoxides was investigated by a kinetic method in 98:2 (v/v) dioxane-water mixture and in water. On the basis of medium, substituent (ρ + 1.03), steric, salt and kinetic isotope effects detailed mechanisms involving a hydroxy-λ4-sulfane intrmediate are proposed. The more reactive sulfonium salts with a five-membered hetero ring are hydrolyzed by water, whereas the sulfonium centre of the less reactive analogues with a six-membered ring is attacked only by OH- ions.
- Nagy, Peter,Csampai, Antal,Szabo, Denes,Varga, Jeno,Harmat, Veronika,Ruff, Ferenc,Kucsman, Arpad
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p. 339 - 349
(2007/10/03)
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- "Crowned" Fe4S4 Clusters as Electrochemical Metal Ion Sensors
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A series of Fe4S4 cluster compounds I, III, and V, in which the cuboidal cluster core is appended with four crown ether thiolate ligands, and II and IV, bearing thiolate ligands without crown ether parts, has been synthesized and characterized. The spectroscopic and electrochemical properties of these compounds are determined by the electronic nature of the thiolate ligands. Only in the case of III, where a very short α-thioacetyl linker was used to connect the crown ether ligands to the cluster core, was a restricted conformational freedom of the ligand observed. A detailed electrochemical study of the influence of alkali and earth alkali metal ions (Li+, Na+, K+, Mg2+, and Ba2+) on the reversible 2-/3- reduction of the cluster compounds was performed. In the case of the crown ether appended clusters I,III, and V, the addition of these metal ions resulted in an anodic shift, i.e. in positive direction, of the reduction potential (modulation effect) and to larger current responses (promotion effect). The magnitude of the modulation effects is determined by the binding affinity of the metal ions in the crown ether ligands, and by the distance between bound metal ions and the redox active cluster core. Variation of the linker between the cluster core and the metal ion binding site resulted in cluster compounds with almost inverse selectivities for e.g. K+ and Ba2+ in the case of I and III. For the large effects found for compound I a lariat binding mode is proposed.
- Gebbink, Robertus J. M. Klein,Klink, Stephen I.,Feiters, Martinus C.,Nolte, Roeland J. M.
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p. 253 - 264
(2007/10/03)
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- Thiazolothiazepine inhibitors of HIV-1 integrase
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A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purified IN than those containing only one carbonyl group. Substitution with electron-donating or -withdrawing groups did not enhance nor abolish potency against purified IN. By contrast, compounds with a naphthalene ring system showed enhanced potency, suggesting that a hydrophobic pocket in the IN active site might accommodate an aromatic system rather than a halogen. The position of sulfur in the thiazole ring appears important for potency against IN, as its replacement with an oxygen or carbon abolished activity. Further extension of the thiazole ring diminished potency. Compounds 1, 19, and 20 showed antiviral activity and inhibited IN within similar concentrations. These compounds inhibited IN when Mn2+ or Mg2+ was used as cofactor. None of these compounds showed detectable activities against HIV-1 reverse transcriptase, protease, virus attachment, or nucleocapsid protein zinc fingers. Therefore, thiazolothiazepines are potentially important lead compounds for development as inhibitors of IN and HIV replication.
- Neamati, Nouri,Turpin, Jim A.,Winslow, Heather E.,Christensen, John L.,Williamson, Karen,Orr, Ann,Rice, William G.,Pommier, Yves,Garofalo, Antonio,Brizzi, Antonella,Campiani, Giuseppe,Fiorini, Isabella,Nacci, Vito
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p. 3334 - 3341
(2007/10/03)
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- Arylthio compounds
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Arylthiol and dithiobisarylamide antibacterial and antiviral agents have the general formula STR1 where A is monocyclic or bicyclic aryl which can contain up to 3 heteroatoms selected from O, S, and N, R1 and R2 are substituent groups, X is STR2 or SO2 NR4 Z, Y is H or SZ when n is 1, a single bond when n is 2; R4 and Z can be hydrogen or alkyl.
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- Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7
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A manufacturing process to prepare two antiretroviral agents that denature the HIV-1 nucleocapsid protein (NCp7) has been developed and demonstrated on a pilot scale. 2,2′-Dithiobis-(benzoyl chloride) (4), prepared from commercially available 2,2′-dithiobis(benzoic acid) (3), was coupled directly with L-isoleucine to give the potential anti-HIV compound [S-(R*,R*)]-2-{[2-[[2-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl] dithio]-benzoyl]amino}-3-methylpentanoic acid (2) thereby eliminating the α-amino acid protection and deprotection steps used in the original synthesis. Compound 2 was oxidized by bromine to a second potential anti-HIV compound [S-(R*,R*)]-3-methyl-2-(3-oxo-3H-benzo[d]isothiazol-2-yl)pentanoic acid (1). The intermediacy of the hydrobromide salt of 1 provided an effective purity control in the production of the pharmaceutical agent. Cost, operational, safety, environmental, and equipment considerations were taken into account during the course of development.
- Fiore, Phillip J.,Puls, Timothy P.,Walker, Jonathan C.
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p. 151 - 156
(2013/09/08)
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- Process for preparation of 2-equivalent 4-arylthio-5-pyrazolone magenta couplers
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A process for preparation of 2-equivalent 4-arylthio-5-pyrazolone magenta couplers comprises the steps of: (i) reacting a 4-equivalent 5-pyrazolone magenta coupler and a diaryldisulfide compound in the presence of 1,8-diazabicyclo-[5,4,0]-undecen-7-ene and an organic solvent to obtain a reaction product between 4-arylthio-5-pyrazolone magenta coupler and 1,8-diazabicyclo-[5,4,0]-undecen-7-ene, and (ii) converting the reaction product with an inorganic acid into the 4-arylthio-5-pyrazolone magenta coupler. The reaction product between the 4-arylthio-5-pyrazolone magenta coupler and the 1,8-diazabicyclo-[5,4,0]-undecen-7-ene is easily formed in high yield and purity. This reaction product, which is insoluble in the reaction solvent, can be easily isolated from the reaction mixture and converted by acidification into the 2-equivalent 4-arylthio-5-pyrazolone magenta coupler in high yield and purity.
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- A new class of anti-HIV-1 agents targeted toward the nucleocapsid protein NCp7: The 2,2'-dithiobisbenzamides
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As part of the National Cancer Institute's Drug Screening Program, a new class of antiretrovirals active against the human immunodeficiency virus HIV-1 has been identified, and the HIV-1 nucleocapsid protein NCp7 was proposed as the target of antiviral action. The 2,2'-dithiobis-[4'-(sulfamoyl)benzanilide] (3x) and the 2,2'-dithiobis(5-acetylamino)benzamide (10) represented the prototypic lead structures. A wide variety of 2,2'-dithiobisbenzamides were prepared and tested for anti-HIV-1 activity, cytotoxicity, and their ability to extrude zinc from the zinc fingers for NCp7. The structure-activity relationships demonstrated that the ability to extrude zinc from NCp7 resided in the 2,2'-dithiobisbenzamide core structure. The 3,3' and the 4,4' isomers were inactive. While many analogs based upon the core structure retained the zinc extrusion activity, the best overall anti-HIV-1 activity was only found in a narrow set of derivatives possessing carboxylic acid, carboxamide, or phenylsulfonamide functional groups. These functional groups were more important for reducing cytotoxicity than improving antiviral potency or activity vs NCp7. All of the compounds with antiviral activity also extruded zinc from NCp7. From this study several classes of low μM anti-HIV agents with simple chemical structures were identified as possible chemotherapeutic agents for the treatment of AIDS.
- Domagala, John M.,Bader, John P.,Gogliotti, Rocco D.,Sanchez, Joseph P.,Stier, Michael A.,Song, Yuntao,Vara Prasad,Tummino, Peter J.,Scholten, Jeffrey,Harvey, Patricia,Holler, Tod,Gracheck, Steve,Hupe, Donald,Rice, William G.,Schultz, Robert
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p. 569 - 579
(2007/10/03)
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- N-Arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective α1-adrenoceptor antagonists
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Novel arylpiperazines were identified as α1-adrenoceptor (AR) subtype- selective antagonists by functional in vitro screening. 3-[4-(ortho- Substituted phenyl)piperazin-1:yl]propylamines were derivatized with N,N- dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4- b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a 'negative screen' for the test antagonists. Binding to α1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the α1-AR subtype prevalent in the human lower urinary tract (pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the α(1D)-AR.
- Elworthy, Todd R.,Ford, Anthony P. D. W.,Bantle, Gary W.,Morgans Jr., David J.,Ozer, Rachel S.,Palmer, Wylie S.,Repke, David B.,Romero, Magarita,Sandoval, Leticia,Sjogren, Eric B.,Talamás, Francisco X.,Vazquez, Alfredo,Wu, Helen,Arredondo, Nicolas F.,Blue Jr., David R.,DeSousa, Andrea,Gross, Lisa M.,Kava, M. Shannon,Lesnick, John D.,Vimont, Rachel L.,Williams, Timothy J.,Zhu, Quan-Ming,Pfister, Jürg R.,Clarke, David E.
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p. 2674 - 2687
(2007/10/03)
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- Isothiazolones
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Isothiazolones having the general structure STR1 where A is a monocyclic or bicyclic ring which may contain up to 3 heteroatoms selected from O, S, and N; R1 and R2 are substituent groups such as alkyl, alkoxy, hydroxy, nitro, cyano, amino, and carboxy; and R5 is alkyl, cycloalkyl, phenyl, and Het. The isothiazolones are useful as anti-retroviral agents, anti-inflammatory agents, and anti-atherosclerotic agents.
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- Alkylation process for preparing azetidinone compound and starting compound therefor
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Novel process for preparing azetidinone compound of the formula [III]: STR1 wherein R1 is H or lower alkyl, R2 and R3 combine together with the adjacent nitrogen to form heterocyclic group, and R4 is protected or unprotected hydroxy-substituted lower alkyl, which comprises reacting an alkanamide compound of the formula [I]: STR2 wherein R1, R2 and R3 are the same as defined above, with a compound of the formula [II]: STR3 wherein L1 is a leaving group and R4 is the same as defined above, in the presence of a base, said compound [III] being useful as synthetic intermediate for 1-methylcarbapenem derivative having excellent antibacterial activity.
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- Azetidinone compound and process for preparation thereof
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There is disclosed an azetidinone compound of the formula [I]: STR1 wherein Ring B is a benzene ring which may have substituent(s), R1 is a hydroxy-substituted lower alkyl group which may have substituent(s), X is oxygen atom and the like, Y is oxygen atom and the like, and Z is a methylene group which may have substituent(s), which is useful as a synthetic intermediate of the 1β-methylcarbapenem-type antibacterial agent.
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- Arylthio compounds
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Antibacterial and antiviral phenylthiols and dithiobisbenzamides have the formula STR1 where n is 1 or 2, Y is hydrogen when n is 1, and a single bond when n is 2; and R1 and R11 are substituent groups, R4 is hydrogen or alkyl, and Z is hydrogen, alkyl, cycloalkyl or sulfamoylphenyl.
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