- Cobalt-Catalyzed, Directed Intermolecular C-H Bond Functionalization for Multiheteroatom Heterocycle Synthesis: The Case of Benzotriazine
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Transition-metal-catalyzed, directed intermolecular C-H bond functionalization is synthetically useful but heavily underexplored in multiheteroatom heterocycle synthesis. Herein we report a cobalt catalytic method for the formation of a three-nitrogen-bearing benzotriazine scaffold via the coupling of arylhydrazine and oxadiazolone. This synthetic protocol features a low-cost base metal catalyst, a maximum number of heteroatoms built into a heterocycle, a distinct synthetic logic for benzotriazines, a superior step economy, and a broad substrate scope.
- Wu, Weiping,Fan, Shuaixin,Li, Tielei,Fang, Lili,Chu, Benfa,Zhu, Jin
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supporting information
p. 5652 - 5657
(2021/08/01)
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- Design, synthesis, and biological evaluation of 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinones as a new series of AMPKɑ1β1γ1 activators
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Adenosine monophosphate-activated protein kinase (AMPK) plays a key role in maintaining whole-body homeostasis and has been regarded as a therapeutic target for the treatment of diabetic nephropathy (DN). Herein, a series of 1,2,4-oxadiazole-containing py
- Xiao, Zhihong,Peng, Yajun,Zheng, Bifeng,Chang, Qi,Guo, Yating,Chen, Zhuo,Li, Qianbin,Hu, Gaoyun
-
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- Efficient synthesis of novel 1-hydroxy-2,4,5-trisubstituted imidazole derivatives via a one-pot, four-component reaction between hydroxylamine, benzonitriles, arylglyoxals and cyclic 1,3-dicarbonyl compounds
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A simple, and efficient procedure for the synthesis of novel 2,5-diaryl-1-hydroxy-1H-imidazol-4-yl derivatives via a one-pot, four-component reaction between hydroxylamine, benzonitriles, arylglyoxals and cyclic 1,3-dicarbonyl compounds (Melrum’s acid or dimedone) in ethanol under reflux conditions without using bases and catalysts is reported. All the products were obtained in good yields and their structures were established from their spectroscopic data.
- Alizadeh-Bami, Farzaneh,Salehzadeh, Mina,Mehrabi, Hossein,Ranjbar-Karimi, Reza
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supporting information
p. 55 - 63
(2019/11/11)
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- Efficient Synthesis of Functionalized Indene Derivatives via Rh(III)-Catalyzed Cascade Reaction between Oxadiazoles and Allylic Alcohols
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A highly efficient rhodium(III)-catalyzed synthesis of novel functionalized indene derivatives has been achieved via C?H activation/intramolecular aldol condensation. This cascade reaction is an atom economical protocol which could be further applied to build more complex compounds. (Figure presented.).
- Zhang, Jing,Sun, Jun-Shu,Xia, Ying-Qi,Dong, Lin
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supporting information
p. 2037 - 2041
(2019/03/28)
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- Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure–Activity Relationships, and Sleep-Promoting Properties in Rats
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The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.
- Brotschi, Christine,Roch, Catherine,Gatfield, John,Treiber, Alexander,Williams, Jodi T.,Sifferlen, Thierry,Heidmann, Bibia,Jenck, Francois,Bolli, Martin H.,Boss, Christoph
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supporting information
p. 1257 - 1270
(2019/06/17)
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- Synthesis and antibacterial evaluation of 3,5-Diaryl-1,2,4-oxadiazole derivatives
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This manuscript reports the synthesis of twenty 3,5-diaryl-1,2,4-oxadiazole derivatives, nine of which are novel compounds. The amidoxime reaction with acyl chlorides obtained from substituted benzoic acids was used. All compounds were tested against five standard (American Type Culture Collection (ATCC)) bacteria: Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Proteus mirabilis and Staphylococcus aureus. Screening assays were carried out using agar-diffusion technique, in which 100 μM heterocyclic compounds solutions (20percent dimethylsulfoxide/water) were employed. The minimum inhibitory concentrations (MIC) of the active compounds were determined by serial dilutions at decreasing concentrations in microtiter plates. The nitrated derivatives gave the best test results, where MIC = 60 μM (E. coli) was the lowest value found for an ortho-nitrated derivative. The activity of these compounds possibly involves a mechanism via free radicals. S. aureus and P. aeruginosa were resistant to all compounds.
- Cunha, Felipe S.,Nogueira, Joseli M. R.,De Aguiar, Alcino P.
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p. 2405 - 2416
(2018/10/20)
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- Synthesis, characterisation and photophysical studies of oxadiazolyl coumarin: A new class of blue light emitting fluorescent dyes
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A library of novel 1, 2, 4-oxadiazole linked coumarin dyes have been synthesised via condensation of corresponding acid 6 and N’-hydroxybenzimidamide 8. This new class of organic compounds were examined for their fluorescent properties and found to emit blue light in the visible region of the spectrum with very high Stoke's shift values. Most of these compounds demonstrated high quantum yields and fluorescence life time in nano-second range which makes them quite lucrative to be used as new fluorescent probes. The highest quantum yield of 0.68 was shown by compound 9j which also shows high Stoke's shift value. The electronic structure of these coumarin-based donor–π–acceptor (D–π–A)-type organic dyes have been examined by Density Functional Theory (DFT). TGA analysis of few of the compounds show that they are stable up to temperature range of 0–245?°C. The synthesised compounds were characterised by NMR and mass spectrometry and the structure of two of these compounds have been confirmed by X-ray crystallography.
- Matta, Akanksha,Bahadur, Vijay,Taniike, Toshiaki,Van der Eycken, Johan,Singh, Brajendra K.
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p. 250 - 260
(2017/02/05)
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- Indazole-oxadiazole derivative, medicinal composition containing derivative, and application of derivative in tumor prevention
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The invention discloses an indazole-oxadiazole derivative with the structure represented by general formula a shown in the description, or a pharmaceutically acceptable salt or solvate thereof. In the formula, X is O or N, Y is N, Z is N or O, and all groups are as defined in the description. The invention also discloses a medicinal composition adopting the derivative as an active component, and a use of the derivative. Compounds synthesized in the invention have an HIF-1 inhibition effect, and most of the compounds have a substantial HIF-1 inhibition effect, have strong in-vivo and in-vitro anti-HIF-1 effect on human colorectal carcinoma cell strains (HCT116) and other tumor cell strains, and can be used for treating tumor diseases.
- -
-
Paragraph 0099; 0100; 0121; 0122
(2017/07/25)
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- Nitrobenzofurazan derivatives of N′-hydroxyamidines as potent inhibitors of indoleamine-2,3-dioxygenase 1
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Tryptophan metabolism through the kynurenine pathway is considered as a crucial mechanism in immune tolerance. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism in the immune system and it is also considered as an important therapeutic target for the treatment of cancer and other diseases that are linked with kynurenine pathway. In this study, a series of nitrobenzofurazan derivatives of N′-hydroxybenzimidamides (1) and N′-hydroxy-2-phenylacetimidamides (2) were synthesized and their inhibitory activities against human IDO1 enzyme were tested using in-vitro and cellular enzyme activity assay. The optimization leads to the identification of potent compounds, 1d, 2i and 2k (IC50 = 39-80 nM), which are either competitive or uncompetitive inhibitors of IDO1 enzyme. These compounds also showed IDO1 inhibition potencies in the nanomolar range (IC50 = 50-71 nM) in MDA-MB-231 cells with no/negligible amount of cytotoxicity. The stronger selectivity of the potent compounds for IDO1 enzyme over tryptophan 2,3-dioxygenase (TDO) enzyme (312-1593-fold) also makes them very attractive for further immunotherapeutic applications.
- Paul, Saurav,Roy, Ashalata,Deka, Suman Jyoti,Panda, Subhankar,Trivedi, Vishal,Manna, Debasis
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p. 364 - 375
(2016/06/13)
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- Novel benzimidazole-oxadiazole hybrid molecules as promising antimicrobial agents
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In the present study, we describe the design and expeditious synthesis of novel 2-aryl-5-(3-aryl-[1,2,4]-oxadiazol-5-yl)-1-methyl-1H-benzo[d]imidazole hybrid molecules as promising antimicrobial agents. The core moiety 2-aryl-ethyl-1H-benzo[d]imidazole-5-
- Shruthi,Poojary, Boja,Kumar, Vasantha,Hussain, Mumtaz Mohammed,Rai, Vaishali M.,Pai, Vinitha R.,Bhat, Mahima,Revannasiddappa
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p. 8303 - 8316
(2016/02/09)
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- Molecular properties prediction and synthesis of new oxadiazole derivatives possessing 3-fluoro-4-methoxyphenyl moiety as potent anti-inflammatory and analgesic agents
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A new series of 1,2,4- and 1,3,4-oxadiazole derivatives possessing 3-fluoro-4-methoxyphenyl moiety were efficiently synthesized and characterized by spectroscopic methods and elemental analysis. All the compounds were evaluated in vivo for their anti-infl
- Dinesha,Viveka, Shivapura,Khandige, Prasanna S.,Nagaraja, Gundibasappa K.
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p. 435 - 443
(2016/02/16)
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- Novel potent HIF-1 inhibitors for the prevention of tumor metastasis: discovery and optimization of 3-aryl-5-indazole-1,2,4-oxadiazole derivatives
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Hypoxia inducible factor-1 (HIF-1) is the key transcription factor of cellular response to hypoxia and plays a critical role in tumor metastasis. We describe here the discovery and a structure-activity relationship study of a series of 3-aryl-5-indazole-1,2,4-oxadiazole derivatives as novel HIF-1 inhibitors. The two most promising compounds 4g and 4h inhibit HIF-1 transcription with IC50 values of 0.62 and 0.55 μM in vitro, respectively, and they exhibit more efficient HIF-1 inhibition in xenograft tumors than YC-1, a potential anticancer drug targeting HIF-1. In addition, they also remarkably prevent the hypoxia-driven migration of SKOV3 cells in vitro and tumor metastasis in vivo. Further investigation of the mechanism revealed that the two inhibitors could decrease HIF-1α and VEGF expression. These results suggest that our newly synthesized HIF-1 inhibitors 4g and 4h are potential therapeutic agents with which to treat tumor metastasis.
- Sheng, Rong,Li, Shan,Lin, Guanyu,Shangguan, Shihao,Gu, Yongchuan,Qiu, Ni,Cao, Ji,He, Qiaojun,Yang, Bo,Hu, Yongzhou
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p. 81817 - 81830
(2015/10/12)
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- Discovery, bioactivity and docking simulation of Vorinostat analogues containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors and antitumor agents
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Abstract In our study, three series of hydroxamate, 2-aminobenzamide, and trifluoromethyl ketone analogues have been designed and synthesized. The synthesized compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against three human cancer cell lines including A549, NCI-H661, and U937. Most analogues exhibited higher antiproliferative activities against human acute myeloid leukemia cell U937 than the other two human lung cancer cell lines. Furthermore, the compounds were examined against HDAC1, 2, and 8 isoforms. Docking study of compounds 6h, 9b, and 10a suggested that they might bind tightly to the binding pocket of HDAC2 and/or HDAC8. The results suggest that these compounds might have potential as lead compounds for the development of anti-tumor drugs with HDACs inhibitory activities.
- Cai, Jin,Wei, Hongtao,Hong, Kwon Ho,Wu, Xiaoqing,Zong, Xi,Cao, Meng,Wang, Peng,Li, Lushen,Sun, Chunlong,Chen, Bo,Zhou, Gaoxing,Chen, Junqing,Ji, Min
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p. 3457 - 3471
(2015/08/03)
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- Discovery and preliminary evaluation of 2-aminobenzamide and hydroxamate derivatives containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors
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Using Entinostat as a lead compound, 2-aminobenzamide and hydroxamate derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against five human cancer cell lines including U937, A549, NCI-H661, MDA-MB-231 and HCT116. 2-Aminobenzamide series of compounds (10a-10j) demonstrated the most significant inhibition against human acute monocytic myeloid leukemia cell line U937, but no or poor activities against two human lung cancer cell lines. Furthermore, the target compounds were screened for their inhibitory activities against HDAC 1, 2, and 8. 2-Aminobenzamide derivatives (10) manifested a higher selectivity for HDAC 1 over HDAC 2, but were not active against HDAC 8. In contrast, most hydroxamate derivatives (11) inhibit HDAC 8 with lower IC50 values than SAHA and Entinostat. Docking study with selected compounds 10f and 11a revealed that the compounds might bind tightly to the binding pockets in HDAC 2 and HDAC 8, respectively. The results suggest that they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting HDACs.
- Cai, Jin,Wei, Hongtao,Hong, Kwon Ho,Wu, Xiaoqing,Cao, Meng,Zong, Xi,Li, Lushen,Sun, Chunlong,Chen, Junqing,Ji, Min
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-
- One-Pot Synthesis of N-Monosubstituted Ureas from Nitriles via Tiemann Rearrangement
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Amidoximes, obtained from the reaction of nitriles with hydroxylamine, underwent Tiemann rearrangement in the presence of benzenesulfonyl chlorides (TsCl or o-NsCl) to form the N-substituted cyanamides. Subsequently, acidic hydrolysis of the cyanamides afforded the corresponding N-monosubstituted ureas. The synthesis of N-monosubstituted ureas from nitriles was accomplished by three steps in one pot, which provides a direct access to versatile N-monosubstituted urea derivatives from a wide variety of nitriles.
- Wang, Chien-Hong,Hsieh, Tsung-Han,Lin, Chia-Chi,Yeh, Wen-Hsiung,Lin, Chih-An,Chien, Tun-Cheng
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supporting information
p. 1823 - 1826
(2015/08/06)
-
- AZETIDINE AMIDE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS
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The present invention relates to azetidine amide derivatives derivatives of formula (I) wherein rings A1 A2 and A3 are as described in the description, to pharmaceutically acceptable salts thereof, to their preparation, to
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-
Page/Page column 46; 47
(2014/09/29)
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- An experimental and theoretical study of reaction mechanisms between nitriles and hydroxylamine
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The industrially relevant reaction between nitriles and hydroxylamine yielding amidoximes was studied in different molecular solvents and in ionic liquids. In industry, this procedure is carried out on the ton scale in alcohol solutions and the above transformation produces a significant amount of unexpected amide by-product, depending on the nature of the nitrile, which can cause further analytical and purification issues. Although there were earlier attempts to propose mechanisms for this transformation, the real reaction pathway is still under discussion. A new detailed reaction mechanistic explanation, based on theoretical and experimental proof, is given to augment the former mechanisms, which allowed us to find a more efficient, side-product free procedure. Interpreting the theoretical results obtained, it was shown that the application of specific imidazolium, phosphonium and quaternary ammonium based ionic liquids could decrease simultaneously the reaction time while eliminating the amide side-product, leading to the targeted product selectively. This robust and economic procedure now affords a fast, selective amide free synthesis of amidoximes.
- V?r?s, Attila,Mucsi, Zoltn,Ban, Zoltn,Timri, Gza,Hermecz, Istvn,Mizsey, Pter,Finta, Zoltn
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supporting information
p. 8036 - 8047
(2015/01/08)
-
- Practical synthesis of N -substituted cyanamides via tiemann rearrangement of amidoximes
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A facile and general synthesis of various N-substituted cyanamides was accomplished by the Tiemann rearrangement of amidoximes with benzenesulfonyl chlorides (TsCl or o-NsCl) and DIPEA.
- Lin, Chia-Chi,Hsieh, Tsung-Han,Liao, Pen-Yuan,Liao, Zhen-Yuan,Chang, Chih-Wei,Shih, Yu-Chiao,Yeh, Wen-Hsiung,Chien, Tun-Cheng
-
supporting information
p. 892 - 895
(2014/03/21)
-
- A novel one-pot synthesis of ferrocenyl-substituted 1,2,4-oxadiazoles
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One-pot synthesis of 5-ferrocenyl-1,2,4-oxadiazoles via the reaction between 3-ferrocenylpropynal and amidoximes is described. 3-Ferrocenylpropynal reacts with a variety of amidoximes in the presence of KOH in refluxing dioxane to afford a broad range of
- Zora, Metin,Kivrak, Arif,Kelgokmen, Yilmaz
-
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- Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype
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We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with 120 nM potency in an antiproliferative assay. Biologi
- Krasavin, Mikhail,Sosnov, Andrey V.,Karapetian, Ruben,Konstantinov, Igor,Soldatkina, Olga,Godovykh, Elena,Zubkov, Fedor,Bai, Ruoli,Hamel, Ernest,Gakh, Andrei A.
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p. 4477 - 4481
(2015/02/19)
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- Design, synthesis and SAR of piperidyl-oxadiazoles as 11β- hydroxysteroid dehydrogenase 1 inhibitors
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The potential roles of 11β-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11β-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl-oxadiazole derivatives as human 11β-HSD1 inhibitors, we explored the structure-activity relationship of several parts of the lead compound. Based on their potency toward human 11β-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11β-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model.
- Xia, Guangxin,You, Xiaodi,Liu, Lin,Liu, Haiyan,Wang, Jianfa,Shi, Yufang,Li, Ping,Xiong, Bing,Liu, Xuejun,Shen, Jingkang
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- COMPOUNDS HAVING AN ETHR INHIBITING ACTIVITY - USE OF SAID COMPOUNDS AS DRUGS - PHARMACEUTICAL COMPOSITION AND PRODUCT CONTAINING SAID COMPOUNDS
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The present invention relates to compounds of Formula (I), wherein R1 is chosen among the following radicals : (II); (III); (IV), (V), (VI) (VII) and n= 1 or 2 and m=1 or 2 with the proviso that m=2 when R1 is (VIII). The present invention also relates to the use thereof as drugs, more particularly in the treatment of mycobacterial infections and more particularly in the treatment of tuberculosis.
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Page/Page column 10
(2013/05/21)
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- Ethionamide boosters. 2. Combining bioisosteric replacement and structure-based drug design to solve pharmacokinetic issues in a series of potent 1,2,4-oxadiazole EthR inhibitors
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Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic.
- Flipo, Marion,Desroses, Matthieu,Lecat-Guillet, Nathalie,Villemagne, Baptiste,Blondiaux, Nicolas,Leroux, Florence,Piveteau, Catherine,Mathys, Vanessa,Flament, Marie-Pierre,Siepmann, Juergen,Villeret, Vincent,Wohlk?nig, Alexandre,Wintjens, René,Soror, Sameh H.,Christophe, Thierry,Jeon, Hee Kyoung,Locht, Camille,Brodin, Priscille,Déprez, Benoit,Baulard, Alain R.,Willand, Nicolas
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experimental part
p. 68 - 83
(2012/03/10)
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- Hydroxamic Acids as Potent Inhibitors of FeII and MnII E. coli Methionine Aminopeptidase: Biological Activities and X-ray Structures of Oxazole Hydroxamate-EcMetAP-Mn Complexes
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New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against the FeII, CoII, and MnII f
- Huguet, Florian,Melet, Armelle,Alves de Sousa, Rodolphe,Lieutaud, Aurelie,Chevalier, Jacqueline,Maigre, Laure,Deschamps, Patrick,Tomas, Alain,Leulliot, Nicolas,Pages, Jean-Marie,Artaud, Isabelle
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scheme or table
p. 1020 - 1030
(2012/07/31)
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- Formation of aromatic amidoximes with hydroxylamine using microreactor technology
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In this contribution, the application of microreactor technology for amidoxime formation is demonstrated, with different aromatic nitriles reacted with a 50% solution of hydroxylamine (HA) under homogeneous conditions to reach full conversion. All reactio
- Voeroes, Attila,Baan, Zoltan,Mizsey, Peter,Finta, Zoltan
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p. 1717 - 1726
(2013/01/15)
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- Clean one-pot synthesis of 1,2,4-oxadiazoles under solvent-free conditions using microwave irradiation and potassium fluoride as catalyst and solid support
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Potassium fluoride was found to be an efficient catalyst and solid support for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles. In this work, a one-pot method for the synthesis of these compounds from the reaction of nitriles with hydroxylamine hydro
- Rostamizadeh, Shahnaz,Ghaieni, Hamid Reza,Aryan, Reza,Amani, Ali Mohammad
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experimental part
p. 494 - 497
(2010/03/03)
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- COMPOUNDS, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN TREATING METABOLIC DISORDERS
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The present invention is directed to novel compounds of formula (I) and their use in treating metabolic diseases.
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Page/Page column 197; 223
(2010/06/22)
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- Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB 2) agonists
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The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB 2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB 1 EC50 > 10 μM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.
- Cheng, Yuan,Albrecht, Brian K.,Brown, James,Buchanan, John L.,Buckner, William H.,DiMauro, Erin F.,Emkey, Renee,Fremeau Jr., Robert T.,Harmange, Jean-Christophe,Hoffman, Beth J.,Huang, Liyue,Huang, Ming,Lee, Josie Han,Lin, Fen-Fen,Martin, Matthew W.,Nguyen, Hung Q.,Patel, Vinod F.,Tomlinson, Susan A.,White, Ryan D.,Xia, Xiaoyang,Hitchcock, Stephen A.
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experimental part
p. 5019 - 5034
(2009/07/19)
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- Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists
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A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)- xanthine derivatives as A2B-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A2B, A 1, A2A, and A3-AdoRs. 8-(1-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (Ki = 1 nM) and selectivity for the A2B-AdoR versus A1, A2A, and A 3-AdoRs (A1/A2B, A2A/A2B, and A3/A2B selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
- Elzein, Elfatih,Kalla, Rao,Li, Xiaofen,Perry, Thao,Parkhill, Eric,Palle, Venkata,Varkhedkar, Vaibahv,Gimbel, Art,Zeng, Dewan,Lustig, David,Leung, Kwan,Zablocki, Jeff
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p. 302 - 306
(2007/10/03)
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- NOVEL ALKYNYL DERIVATIVES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
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The present invention relates to novel compounds of formula (I) wherein W, n, X and W’ are defined in the description; invention compounds are modulators of metabotropic glutamate receptors - subtype 5 (“mGluR5”) which are useful for the treatment of central nervous system disorders as well as other disorders modulated by mGluR5 receptors.
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Page/Page column 113
(2008/06/13)
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- Antikinetoplastid activity of 3-aryl-5-thiocyanatomethyl-1,2,4-oxadiazoles
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A series of 5-thiocyanatomethyl- and 5-alkyl-3-aryl-1,2,4-oxadiazoles were synthesized and evaluated for their activity against kinetoplastid parasites. Formation of the oxadiazole ring was accomplished through the reaction of benzamidoximes with acyl chlorides, while the thiocyanate group was inserted by reacting the appropriate 5-halomethyl oxadiazole with ammonium thiocyanate. The thiocyanate-containing compounds possessed low micromolar activity against Leishmania donovani and Trypanosoma brucei, while the 5-alkyl oxadiazoles were less active against these parasites. 3-(4-Chlorophenyl)-5-(thiocyanatomethyl)-1, 2,4-oxadiazole (compound 4b) displayed modest selectivity for L. donovani axenic amastigote-like parasites over J774 macrophages, PC3 prostate cancer cells, and Vero cells (6.4-fold, 3.8-fold, and 9.1-fold, respectively), while 3-(3,4-dichlorophenyl)-5-(thiocyanatomethyl)-1,2,4-oxadiazole (compound 4h) showed 30-fold selectivity against Vero cells but was not selective against PC3 cells. In a murine model of visceral leishmaniasis, compound 4b decreased liver parasitemia caused by L. donovani by 48% when given in five daily i.v. doses at 5mg/kg and by 61% when administered orally for 5days at 50mg/kg. These results indicate that aromatic thiocyanates hold promise for the treatment of leishmanial infections if the selectivity of these compounds can be improved.
- Cottrell, Denise M.,Capers, Jeffrey,Salem, Manar M.,DeLuca-Fradley, Kate,Croft, Simon L.,Werbovetz, Karl A.
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p. 2815 - 2824
(2007/10/03)
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- Structure-activity relationships of acyloxyamidine cytomegalovirus DNA polymerase inhibitors
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This paper describes the structure-activity relationships of a new class of cytomegalovirus DNA polymerase inhibitors having two aryl groups joined by an acyloxyamidine linker. Examination of a series of analogues in which the terminal groups are varied r
- Tucker, John A.,Clayton, Terrance L.,Chidester, Connie G.,Schulz, Martin W.,Harrington, Leigh E.,Conrad, Steven J.,Yagi, Yoshihiko,Oien, Nancee L.,Yurek, David,Kuo, Ming-Shang
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p. 601 - 615
(2007/10/03)
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- Pesticidal tin amidoximes
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Compounds of the formula: STR1 wherein R1 is lower alkyl of 1 to 6 carbon atoms; alkyl-thioalkylene of 2 to 5 carbon atoms; aryl of 6 to 10 carbon atoms; aralkyl of 7 to 12 carbon atoms; arylthioalkyl of 7 to 11 carbon atoms; or substituted ary
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