- Polarized ketene dithioacetals-versatile synthons for different heterocycles
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The reactivity of polarized ketene dithioacetals to develop a variety of heterocycles under different conditions was studied.
- Venkatesh,Premakumari,Padmaja,Padmavathi
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- The reactivity of gem cyanoester ketene dithiolates towards the development of potent antioxidant heterocycles
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The reactivity of gem cyanoester ketene dithiolates towards the development of a variety of heterocycles was studied and tested for antioxidant property. The compounds bis benzoxazolylmethylthiomethylene pyrazoles and isoxazoles displayed excellent radical scavenging activity when compared with the standard ascorbic acid.
- Padmavathi, Venkatapuram,Venkatesh, Bhumireddy Chinnachennaiahgari,Muralikrishna, Akkarapalli,Padmaja, Adivireddy
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- Synthesis and antioxidant activity of a new class of bis and tris heterocycles
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A series of novel heterocycles, bisbenzoxazolyl/benzothiazolyl/ benzimidazolyl pyrazoles/isoxazoles/pyrimidines were synthesized and evaluated for their antioxidant activity. The bisbenzoxazolylisoxazole 10 exhibited good antioxidant activity when compared with the standard ascorbic acid.
- Padmavathi, Venkatapuram,Venkatesh, Bhumireddy Chinnachennaiahgari,Muralikrishna, Akkarapalli,Padmaja, Adivireddy
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- Exploring Steric Effects of Zinc Complexes Bearing Achiral Benzoxazolyl Aminophenolate Ligands in Isoselective Polymerization of rac-Lactide
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A series of tridentate achiral benzoxazolyl-based aminophenolate zinc complexes, LZnN(SiMe3)2 (L = 2-{[benzoxazoly-CH2N(R3)-]CH2}-6-R1-4-R2-C6H2O, R1/
- Hu, Jianwen,Kan, Chao,Ma, Haiyan
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- Excited-state intramolecular single and double proton transfer emission of 2,5-bis(benzoxazol-2-yl)thiophene-3,4-diol
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In this work, excited-state intramolecular single proton transfer emission (S-PTE) and double proton transfer emission (D-PTE) are presented by employing 2,5-bis(benzoxazol-2-yl)thiophene-3,4-diol (1) as a prototype. 1 has been strategically designed and synthesized in an aim to explore single proton transfer and double proton transfer in the excited state. In solution 1 exhibits the lowest lying S0 → S1 absorption at ~395 nm. Upon excitation, two large Stokes shifted emission bands maximized at 475 nm and 550 nm are resolved, which are ascribed to the tautomer emission resulting from single proton transfer and double proton transfer isomers, respectively. It is found that solvents have greatly influenced on excited-state intramolecular proton transfer emission.
- Hao, Yongchao,Chen, Yi
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- COMPOUNDS HAVING PDE9A INHIBITORY ACTIVITY, AND PHARMACEUTICAL USES THEREOF
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The present invention provides a compound having a specific chemical structure and having PDE9A inhibitory activity, or a pharmaceutically acceptable salt thereof. The present invention provides a composition containing the compound or a pharmaceutically acceptable salt thereof. The present invention provides a pharmaceutical use, for treating or preventing PDE9A-related diseases, of the compound according to the present invention, a salt thereof, and a composition containing the compound or salt. The present invention also provides a method for treating or preventing PDE9A-related diseases, the method comprising administering an effective amount of the compound according to the present invention, a salt thereof, or a composition containing the compound or salt to a subject in need of treatment.
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Paragraph 0097-0098
(2021/10/15)
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- Benzoxazole derivative and preparation method and application thereof
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The invention provides a benzoxazole derivative and a preparation method and application thereof. Studies discover that the benzoxazole derivative provided herein has good P2Y14 inhibitory activity and anti-inflammatory activity, and is suitable for the p
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Paragraph 0062-0065
(2019/04/17)
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- Anti-oligomerization sheet molecules: Design, synthesis and evaluation of inhibitory activities against α-synuclein aggregation
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Aggregation of α-synuclein (α-Syn) play a key role in the development of Parkinson Disease (PD). One of the effective approaches is to stabilize the native, monomeric protein with suitable molecule ligands. We have designed and synthesized a series of sheet-like conjugated compounds which possess different skeletons and various heteroatoms in the two blocks located at both ends of linker, which have good π-electron delocalization and high ability of hydrogen-bond formation. They have shown anti-aggregation activities in vitro towards α-Syn with IC50 down to 1.09 μM. The molecule is found binding in parallel to the NACore within NAC domain of α-Syn, interfering aggregation of NAC region within different α-Syn monomer, and further inhibiting or slowing down the formation of α-Syn oligomer nuclei at lag phase. The potential inhibitor obtained by our strategy is considered to be highly efficient to inhibit α-Syn aggregation.
- Liu, Hao,Chen, Li,Zhou, Fei,Zhang, Yun-Xiao,Xu, Ji,Xu, Meng,Bai, Su-Ping
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supporting information
p. 3089 - 3096
(2019/06/14)
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- Synthesis of Benzazolyl Pyrimidines Under Ultrasonication and Their Antimicrobial Activity
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(1) The benzoxazolyl/benzothiazolyl/benzimidazolyl pyrimidines were prepared under ultrasonication in the presence of pyridine/dimethylaminopyridine and triethylamine. (2) Better yields were recorded in 4-(N,N-dimethylamino)pyridine and Et3N. (3) The presence of electron withdrawing chloro, bromo, and nitro substituents enhanced antimicrobial activity (13c, 13e, 14e: minimum inhibitory concentration?=?6.25?μg/well against Bacillus subtilis; 13e, 14e: minimum inhibitory concentration?=?6.25?μg/well against Aspergillus niger).
- Kayathi, Narendra Babu,Sowmya, Donthamsetty V.,Adivireddy, Padmaja,Venkatapuram, Padmavathi
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p. 1024 - 1032
(2018/02/21)
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- Synthesis, antifungal activities and molecular docking studies of benzoxazole and benzothiazole derivatives
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Based on benzoxazole and benzothiazole scaffold as an important pharmacophore, two series of 2-(aryloxymethyl) benzoxazole and benzothiazole derivatives were synthesized and their antifungal effects against eight phytopathogenic fungi were evaluated. Compounds 5a, 5b, 5h, and 5i exhibited significant antifungal activities against most of the pathogens tested. Especially 5a, 5b, 5h, 5i, 5j, and 6h inhibited the growth of F. solani with IC50 of 4.34–17.61 μg/mL, which were stronger than that of the positive control, hymexazol (IC50 of 38.92 μg/mL). 5h was the most potent inhibitor (IC50 of 4.34 μg/mL) against F. Solani, which was about nine times more potent than hymexazol. Most of the test compounds displayed significant antifungal effects against B. cinerea (IC50 of 19.92–77.41 μg/mL), among them, 5a was the best one (IC50 of 19.92 μg/mL). The structure-activity relationships (SARs) were compared and analyzed. The result indicates that the electron-drawing ability and position of the substituents have a significant impact on biological activities. Furthermore, docking studies were carried out on the lipid transfer protein sec14p from S. cerevisiae, and preliminarily verified the antifungal activities. Taken together, these results provide 2-(phenoxymethyl)benzo[d]oxazole as an encouraging framework that could lead to the development of potent novel antifungal agents.
- Luo, Bo,Li, Ding,Zhang, An-Ling,Gao, Jin-Ming
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- Design, synthesis, and biological evaluation of N,N-disubstituted-4-arylthiazole-2-methylamine derivatives as cholesteryl ester transfer inhibitors
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Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability.
- Wang, Xinran,Lin, Xuehua,Xu, Xuanqi,Li, Wei,Hao, Lijuan,Liu, Chunchi,Zhao, Dongmei,Cheng, Maosheng
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- Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents
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Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Aβ1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50 = 215 nM), and also selectively complexes Cu2+. Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold.
- Knez, Damijan,Brus, Boris,Coquelle, Nicolas,Sosi?, Izidor,?ink, Roman,Brazzolotto, Xavier,Mravljak, Janez,Colletier, Jacques-Philippe,Gobec, Stanislav
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supporting information
p. 4442 - 4452
(2015/08/03)
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- Microwave-assisted α-halogenation of 2-methylquinolines with tetrabutylammonium iodide and 1,2-dichloroethane (1,2-dibromoethane)
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A simple and efficient methodology permitting the halogenation of 2-methylquinolines into 2-(chloromethyl)quinolines or 2-(bromomethyl)quinolines in the tetrabutylammonium iodide and 1,2-dichloroethane (1,2-dibromoethane) system has been developed for the first time. The halogenation can be rapidly completed with good to excellent yields and high selectivity under microwave irradiation.
- Xie, Yuanyuan,Li, Lehuan
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supporting information
p. 3892 - 3895
(2014/07/08)
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- Indoles via Knoevenagel-Hemetsberger reaction sequence
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A series of substituted indoles have been synthesized by the sequential reaction of aromatic aldehydes with ethyl azidoacetate in the presence of sodium ethoxide to form the corresponding ethyl α-azido-β-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process). The isolated yields of the ethyl α-azido-β-arylacrylates were significantly increased when employing the sacrificial electrophile ethyl trifluoroacetate. 1H NMR and coupled 1H-13C NMR analysis of the ethyl α-azido-β-arylacrylates indicate that the condensation is stereospecific - only the Z-isomer could be detected. Solvent mediated thermal treatment of the meta-substituted ethyl α-azido-β- arylacrylates resulted in the formation of both the 5- and 7- substituted indoles - the 5-regioisomer being slightly favored over the 7-regioisomer. Analogous thermal treatment of (2Z, 2Z′)-diethyl 3,3′-(1,3- phenylene)bis(2-azidoacrylate) and (2Z, 2Z′)-diethyl 3,3′-(1,4- phenylene)bis(2-azidoacrylate) exclusively produced pyrroloindoles, diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate and diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate, respectively. Results are also reported which indicate that the α-azido-β-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior purification.
- Heaner Iv, William L.,Gelbaum, Carol S.,Gelbaum, Leslie,Pollet, Pamela,Richman, Kent W.,Dubay, William,Butler, Jeffrey D.,Wells, Gregory,Liotta, Charles L.
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p. 13232 - 13242
(2013/09/02)
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- Heterocyclization reactions of ketene dithiolates
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The reaction of ketene dithiolates in the presence of K2CO3 lead to bisthioalkylated products and thienothiophene derivatives depending on the strength of the base. The 1,5-diamino groups in thienothiophene compounds are subjected to heterocyclization under PTC conditions to get a variety of fused heterocycles.
- Venkatesh, Bhumireddy Chinnachennaiahgari,Basha, Nabhubygari Mahaboob,Padmaja, Adivireddy,Padmavathi, Venkatapuram
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p. 665 - 670
(2013/07/05)
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- Synthesis of some new oxazolinyl/thia-zolinyl/imidazolinyl-benzoxazoles, benzothiazoles and benzimidazoles
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A new class of oxazolinyl/thiazolinyl/imidazolinyl-benzo- xazoles/benzothiazoles/benzimidazoles have been prepared by exploiting the respective heterocyclic sulfonyl acetic acid methyl ester functionality with different nucleophiles using samarium(III) chloride.
- Seenaiah,Venkatesh,Padmaja,Padmavathi
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p. 942 - 948
(2013/08/15)
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- Functionalized orthoesters as powerful building blocks for the efficient preparation of heteroaromatic bicycles
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By combining substituted anilines with functionalized orthoesters, an efficient and connective methodology for the preparation of benzoxazole, benzothiazole, and benzimidazole derivatives has been established. The versatility of this approach enables the development of new libraries of heterocycles containing multifunctional sites.
- Bastug, Gulluzar,Eviolitte, Christophe,Markó, István E.
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supporting information; experimental part
p. 3502 - 3505
(2012/08/08)
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- Discovery and extensive in vitro evaluations of NK-HDAC-1: A chiral histone deacetylase inhibitor as a promising lead
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Herein, further SAR studies of lead compound NSC746457 (Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X. W.; Chen, M.; Fang, L. Y.; Sun; D. X.; Wang. P. G.J. Med. Chem. 2008, 51, 7417-7427) were performed, including the replacement of the trans-styryl moiety with a 2-substituted benzo-hetero aromatic ring and the introduction of a substituent onto the central methylene carbon. A promising chiral lead, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3- triazol-4-yl)-N-hydroxyacrylamide (12, NK-HDAC-1), was discovered and showed about 1 order of magnitude more potency than SAHA in both enzymatic and cellular assays. For the in vitro safety tests, NK-HDAC-1 was far less toxic to nontransformed cells than tumor cells and showed no significant inhibition activity against CYP-3A4. The pharmaceutical properties (LogD, solubility, liver micrsomal stability (t1/2), plasma stability (t1/2), and apparent permeability) strongly suggested that NK-HDAC-1 might be superior to SAHA in bioavailability and in vivo half-life.
- Hou, Jingli,Li, Zhonghua,Fang, Qinghong,Feng, Congran,Zhang, Hanwen,Guo, Weikang,Wang, Huihui,Gu, Guoxian,Tian, Yinping,Liu, Pi,Liu, Ruihua,Lin, Jianping,Shi, Yi-Kang,Yin, Zheng,Shen, Jie,Wang, Peng George
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supporting information; experimental part
p. 3066 - 3075
(2012/06/01)
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- Synthesis and in vitro evaluation of fluorinated styryl benzazoles as amyloid-probes
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The formation of proteinaceous aggregates is a pathognomonic hallmark of several neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. To date, the final diagnostic for these diseases can only be achieved by immunostaining of post-mortem brain tissues with the commonly used congo red and Thioflavin T/S amyloid-dyes. The interest in developing amyloid-avid radioprobes to be used for protein aggregates imaging by positron emission tomography has grown substantialy, due to the promise in assisting diagnosis of these disorders. To this purpose, the present work describes the synthesis and characterization of four novel fluorinated styryl benzazole derivatives 1-4 by means of the Wittig reaction, as well as their in vitro evaluation as amyloid-probing agents. All compounds were obtained as mixtures of geometric E and Z isomers, with the preferable formation of the E isomer. Photoisomerization reactions allowed for the maximization of the minor Z isomers. The authentic 1-4E/Z isomers were isolated after purification by column chromatography under dark conditions. Profiting from the fluorescence properties of the different geometric isomers of 1-4, their binding affinities towards amyloid fibrils of insulin, α-synuclein and β-amyloid peptide were also measured. These compounds share similarities with Thioflavin T, interacting specifically with fibrillary species with a red-shift in the excitation wavelengths along with an increase in the fluorescence emission intensity. Apparent binding constants were determined and ranged between 1.22 and 23.96 μM-1. The present data suggest that the novel fluorinated styryl benzazole derivatives may prove useful for the design of 18F-labeled amyloid radioprobes.
- Ribeiro Morais, Goreti,Vicente Miranda, Hugo,Santos, Isabel C.,Santos, Isabel,Outeiro, Tiago F.,Paulo, Antonio
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scheme or table
p. 7698 - 7710
(2012/01/03)
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- Design and synthesis of antifungal benzoheterocyclic derivatives by scaffold hopping
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The incidence of invasive fungal infections and associated mortality is increasing dramatically. Although azoles are first-line antifungal agents, cross-resistance and hepatic toxicity are their two major limitations. The discovery of novel non-azole lead compounds will be helpful to overcome these problems. On the basis of our previously reported benzopyran non-azole CYP51 inhibitor, scaffold hopping was used to design structurally diverse new compounds and expand the structure-activity relationships of the lead structure. Five kinds of scaffolds, namely benzimidazole, benzoxazole, benzothiazole, quinazolin-4-one and carboline, were chosen for synthesis. In vitro antifungal activity data and results from molecular docking revealed that the scaffold was important for the antifungal activity. Several compounds showed potent activity against both standard and clinically resistant fungal pathogens, suggesting that they can serve as a good starting point for the discovery of novel antifungal agents.
- Sheng, Chunquan,Che, Xiaoying,Wang, Wenya,Wang, Shengzheng,Cao, Yongbing,Yao, Jianzhong,Miao, Zhenyuan,Zhang, Wannian
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scheme or table
p. 1706 - 1712
(2011/05/06)
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- New 1,2,4-triazine derivatives and biological applications thereof
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The invention relates to new 1,2,4-triazine derivatives of formula (I): wherein A, B, R2 and Y are defined in the application, their preparation and intermediates, their use as drugs and pharmaceutical compositions and associations containing them. The compounds of formula (I) are capable of inhibiting bacterial heptose synthesis.
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Page/Page column 38-39
(2010/01/29)
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- Benz(2-heteroaryl)cyanoximes and their Tl(i) complexes: New room temperature blue emitters
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A series of five 2-heteroarylcyanoximes such as: α-oximino-(2- benzimidazolyl)acetonitrile (HBIHCO), α-oximino-(N-methy-l-2- benzimidazolyl)acetonitrile (HBIMCO), α-oximino-(2-benzoxazolyl) acetonitrile (HBOCO), α-oximino-(2-benzothiazolyl)acetonitrile (HBTCO) and α-oximino-(2-quinolyl)acetonitrile (HQCO) and their monovalent thallium(i) complexes were synthesized and characterized using spectroscopic methods (1H, 13C NMR, IR, UV-visible, mass-spectrometry) and X-ray analysis. The HBIMCO (as monohydrate) adopts planar trans-anti configuration in the solid state. The crystal structure of "HBOCO" revealed the presence of nitroso anion a, BOCO-, and protonated oxime cation b, H2BOCO+, that form a H-bonded dimer in the unit cell. Both molecules adopt planar structures, but different configurations: cis-anti in the molecule a, and trans-anti for b. This is the first reported case of a zwitterionic pair in oximes and the coexistence of the two geometrical cis/trans isomers in the same crystal. All 2-heteroarylcyanoximes form yellow anions upon deprotonation, which exhibit significant negative solvatochromism in solution. Heterogeneous reactions between hot aqueous solutions of Tl 2CO3 and solid protonated 2-heteroarylcyanoximes HL afford yellow TlL. The crystal structure of Tl(BTCO) shows the formation of centrosymmetrical dimers, which connect with each other to form a double-stranded one-dimensional coordination polymer. The oxygen atom of the oxime group acts as a bridge between the three different Tl(i) centers. The anion is non-planar and adopts a trans-anti configuration in the complex. The polymeric motif in the complex represents a ladder-type structure. Staggered π-π interactions between benzothiazolyl groups provide additional stabilization of the structure. Both organic ligands and their Tl(i) complexes exhibit strong room temperature blue emission in the solid state.
- Ilkun, Olesya T.,Archibald, Stephen J.,Barnes, Charles L.,Gerasimchuk, Nikolay,Biagioni, Richard,Silchenko, Svitlana,Gerasimchuk, Olga A.,Nemykin, Victor N.
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supporting information; scheme or table
p. 5715 - 5729
(2009/02/07)
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- PIPERIDINONES USEFUL IN THE TREATMENT OF INFLAMMATION
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There is provided compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, m and n have meanings given in the description, and pharmaceutically acceptable derivatives thereof, which compounds are useful in the treatment of diseases and conditions associated with inflammation.
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Page/Page column 103-104
(2008/12/07)
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- NITROGENOUS CYCLIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
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The present invention provides a novel compound having a superior calcium antagonism, in particular, a neuron-selective calcium antagonism. Namely, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. In the formula, Ar indicates an optionally substituted 5- to 14-membered aromatic ring etc.; the ring A indicates any one ring selected from a piperazine, a homopiperazine, a piperidine and the like; the ring B indicates an optionally substituted C3-14 hydrocarbon ring etc.; E indicates a single bond, a group represented by the formula -CO-, etc.; X indicates a single bond, an oxygen atom etc.; R1 indicates a hydrogen atom, a halogen atom, a hydroxyl group etc.; and D1, D2, W1 and W2 are the same as or different from each other and each represents a single bond or an optionally substituted C1-6 alkylene chain.
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- Synthesis and reactivity of halogeno-difluoromethyl aromatics and heterocycles: Application to the synthesis of gem-difluorinated bioactive compounds
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In an effort to prepare new fluorine-containing compounds which are active against HIV, and based on the electrochemical reduction of a series of bromodifluoromethyl compounds, the tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reduct
- Burkholder, Conrad R.,Dolbier Jr., William R.,Médebielle, Maurice
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- The syntheses of nonnucleoside, HIV-1 reverse transcriptase inhibitors containing a CF2 group: The SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole with the anions derived from heterocyclic thiols and phenolic compounds
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In an effort to prepare new fluorine-containing compounds which are active against HIV, the SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole (5) with the anions of heterocyclic thiols and phenolic compounds were carried out. The products (6
- Burkholder, Conrad R.,Dolbier Jr., William R.,Médebielle, Maurice
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p. 369 - 376
(2007/10/03)
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- Facile synthesis of 2-substituted benzoxazoles via ketenes
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The generation of diphenyl-, phenyl-, phenoxy-, and chloroketenes by treatment of the corresponding acid chlorides with triethylamine in the presence of 2-aminophenol resulted in good yields of 2-substituted benzoxazoles.
- Olagbemiro,Agho,Abayeh,Amupitan
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p. 337 - 338
(2007/10/03)
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- SYNTHESIS OF 2-(4-ARYL-1E,3E-BUTADIENYL)BENZOXAZOLES BY THE HORNER-WADSWORTH-EMMONS REACTION
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2-(4-Aryl-1E,3E-butadienyl)benzoxazole derivatives were synthesized by the Horner-Wadsworth-Emmons reaction of 2-phosphorylmethylbenzoxazoles with cinnamaldehydes in fair to good yield.
- Kosaka, Takatoshi,Wakabayashi, Toshio
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p. 477 - 486
(2007/10/02)
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- N-quinolinyl alkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing class III antiarrhythmic activity
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This invention relates to N-heteroalkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing anti-arrhythmic activity, to pharmaceutical compositions and to methods for production thereof.
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- Substituted benzimidazole derivatives possessing Class III antiarrhythmic activity
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This invention relates to N-heteroalkyl-substituted 1-aryloxy-2-propanolamine and proplyamine derivatives possessing anti-arrhythmic activity, to pharmaceutical compositions and to method for production thereof.
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- Leukotriene D4 antagonists and 5-lipoxygenase inhibitors. Synthesis of benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters.
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A series of novel benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters has been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte 5-lipoxgenase (LO) in vitro and as inhibitors of leukotriene D4 (LTD4) and ovalbumin (OA) induced bronchospasm in the guinea pig (GP) in vivo. In general, inhibitory activity against 5-LO, LTD4, and OA was broadest for benzthiazole-containing analogues (benzthiazole greater than benzimidazole much greater than benzoxazole, benzofuran). The most potent 5-LO inhibitor, 4-[[3-(2-benzthiazolylmethoxy)-phenyl]hydroxyamino]-4-oxobutanoic acid methyl ester (7), had an IC50 of 0.36 microM. Compound 7, however, was inactive vs. OA. The most potent compound in vivo, 4-[[3-[(1-methyl-2-benzimidazolyl)methoxy]phenyl]-amino] -4-oxobutanoic acid methyl ester 4, inhibited both LTD4- and OA-induced bronchospasm by 83% and 60%, respectively, at 50 mg/kg intraduodenally. Compound 4 was studied in the Ames assay employing five strains of bacteria (TA1535, TA1537, TA1538, TA98, and TA100) with and without S-9 rat liver enzyme metabolic activation, and there was no significant number of reversions noted.
- Musser,Kubrak,Chang,DiZio,Hite,Hand,Lewis
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p. 400 - 405
(2007/10/02)
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