- 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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- 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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- Synthesis of 2,4-Disubstituted Imidazoles via Nucleophilic Catalysis
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A convergent, microwave-assisted protocol for the synthesis of disubstituted NH-imidazoles via nucleophilic catalysis is described. The substituted imidazoles are accessed via the intramolecular addition of a variety of amidoxime substrates to activated a
- Camp, Jason E.,Dunsford, Jay J.,Gill, Duncan M.,Ngwerume, Simbarashe,Saunders, Alexandra R.,Shabalin, Dmitrii A.
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supporting information
p. 797 - 800
(2020/05/19)
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- Synthesis and evaluation of new 1,2,4-oxadiazole based trans- acrylic acid derivatives as potential PPAR-alpha/gamma dual agonist
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Diabetes is a ubiquitously a metabolic disorder and life-threatening disease. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors which acts as transcription factors to regulate lipid and glucose metabolism. PPAR alpha/gamma dual agonists tend to corroborate the functions of both thiazolidinediones and fibrates and they hold substantial promise for ameliorating the type 2 diabetic treatments and providing potential therapeutic diabetic interventions. New 1,2,4-oxadiazole based trans- acrylic acid derivatives compounds possessing aryl/methylene linker in between pharmacophore head and lipophilic tail for dual PPAR-alpha/gamma agonists are studied. AutoDock Vina used for potential PPAR alpha/gamma dual agonists and 6 compounds 9a, 9g, 9 m, 9n, 9o, and 9r were identified comparable to PPAR gamma agonist Pioglitazone on the basis of their affinity scores and further their in-silico toxicity and in-silico ADME properties. The selected compounds showed better-calculated lipophilicity (iLogP) was found to be 0.92 to 3.19. Compound 9n and 9a were found to be most potent on both PPAR alpha and gamma receptors with EC50 of 0.07 ± 0.0006 μM, 0.06 ± 0.0005 μM and 0.781 ± 0.008 μM, 3.29 μM ± 0.03 respectively as better to pioglitazone having EC50 of 32.38 ± 0.2 and 38.03 ± 0.13 for both receptors. The in-vivo evaluation found to reduce the plasma glucose level and total cholesterol level significantly in diabetic rats compared to pioglitazone at 5 mg/kg/day dose for 7 days of treatment. Thus, trans- acrylic acid derivatives can be further developed as oral therapeutic agents for diabetic interventions as PPAR alpha/gamma dual agonists.
- Bhat, Sana,Bhat, Zahid Rafiq,Gupta, Jeena,Kaur, Jaskiran,Kaur, Paranjeet,Khatik, Gopal L.,Khurana, Navneet,Kumar, Rajan,Kumar, Rakesh,Tikoo, Kulbhushan
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- KCNT1 INHIBITORS AND METHODS OF USE
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The present invention is directed to, in part, compounds and compositions useful for preventing and/or treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and/or a gain-of-function mutation in a gene (e.g., KCNT1). Methods of treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and/or a gain-of-function mutation in a gene such as KCNT1 are also provided herein.
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Paragraph 000700
(2020/11/23)
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- Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment
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An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly
- Krasavin, Mikhail,Shetnev, Anton,Sharonova, Tatyana,Baykov, Sergey,Kalinin, Stanislav,Nocentini, Alessio,Sharoyko, Vladimir,Poli, Giulio,Tuccinardi, Tiziano,Presnukhina, Sofia,Tennikova, Tatiana B.,Supuran, Claudiu T.
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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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- Novel 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazoles to investigate the activation of the α7 nicotinic acetylcholine receptor subtype: Synthesis and electrophysiological evaluation
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α7 nicotinic acetylcholine receptors (nAChRs) are relevant therapeutic targets for a variety of disorders including neurodegeneration, cognitive impairment, and inflammation. Although traditionally identified as an ionotropic receptor, the α7 subtype showed metabotropic-like functions, mainly linked to the modulation of immune responses. In the present work, we investigated the structure-activity relationships in a set of novel α7 ligands incorporating the 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole scaffold, i.e. derivatives 21a-34a and 21b-34b, aiming to identify the structural requirements able to preferentially trigger one of the two activation modes of this receptor subtype. The new compounds were characterized as partial and silent α7 nAChR agonists in electrophysiological assays, which allowed to assess the contribution of the different groups towards the final pharmacological profile. Overall, modifications of the selected structural backbone mainly afforded partial agonists, among them tertiary bases 27a-33a, whereas additional hydrogen-bond acceptor groups in permanently charged ligands, such as 29b and 31b, favored a silent desensitizing profile at the α7 nAChR.
- Quadri, Marta,Silnovi?, Almin,Matera, Carlo,Horenstein, Nicole A.,Stokes, Clare,De Amici, Marco,Papke, Roger L.,Dallanoce, Clelia
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p. 207 - 228
(2018/10/23)
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- Structure-activity and structure-property relationships of novel Nrf2 activators with a 1,2,4-oxadiazole core and their therapeutic effects on acetaminophen (APAP)-induced acute liver injury
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The antioxidant function induced by Nrf2 protects the liver from damage. We found a novel Nrf2 activator named compound 25 via structural modification of compound 1 we previously reported. In vitro, compound 25 induced Nrf2 transport into the nucleus and protected hepatocyte L02 cells from APAP-induced cytotoxicity via activating the Nrf2-ARE signaling pathway. In vivo, 25 exhibited therapeutic effects in a mouse model of acute liver injury induced by acetaminophen (APAP) by up-regulating Nrf2-dependent antioxidases and down-regulating liver injury markers in serum. Together, these results indicated that 25 is a potent Nrf2/ARE activator both in vitro and in vivo. The drug-like properties of compound 25 further revealed its potential for development as a therapeutic drug against acute liver injury.
- Xu, Li-Li,Wu, Yu-Feng,Wang, Lei,Li, Cui-Cui,Li, Li,Di, Bin,You, Qi-Dong,Jiang, Zheng-Yu
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p. 1376 - 1394
(2018/09/13)
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- Cobalt(III)-Catalyzed Oxadiazole-Directed C-H Activation for the Synthesis of 1-Aminoisoquinolines
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Aromatic heterocycles have been identified as effective directing groups (DGs) in C-H functionalization but can be retained as undesired bulky substituents in the final products. Herein, we report a Co(III)-catalyzed 1-aminoisoquinoline synthesis strategy based on oxadiazole-directed aromatic C-H coupling with alkynes and a subsequent redox-neutral C-N cyclization reaction. This labile N-O bond-based protocol has allowed the toleration of a broad range of functional groups.
- Yang, Fan,Yu, Jiaojiao,Liu, Yun,Zhu, Jin
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supporting information
p. 2885 - 2888
(2017/06/07)
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- Oxadiazolone-Enabled Synthesis of Primary Azaaromatic Amines
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Despite their tremendous synthetic and pharmaceutical utility, primary azaaromatic amines remain elusive for access based on a generally applicable C-H functionalization strategy. An oxadiazolone-enabled approach is reported for convenient entry into N-unsubstituted 1-aminoisoquinolines through Co(III)-catalyzed redox-neutral, step-, atom-, and purification-economic C-H functionalization with alkynes. A 15N labeling experiment reveals the effectiveness of both oxadiazolone N atoms as directing sites. The installed primary amine can be harnessed as a synthetically useful handle for attachment of divergent appendages.
- Yu, Xiaolong,Chen, Kehao,Yang, Fan,Zha, Shanke,Zhu, Jin
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supporting information
p. 5412 - 5415
(2016/11/06)
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- Discovery of highly potent triazole antifungal agents with piperidine-oxadiazole side chains
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Due to increasing incidence and mortality of invasive fungal infections, discovery and development of new generations of antifungal agents represents a challenging task. On the basis of our previously reported triazole-benzyloxypiperidinyl lead compound, a series of novel triazole antifungal agents containing piperidine-oxadiazole side chains were rationally designed and synthesized. Most of the target compounds showed excellent inhibitory activity against clinically important fungal pathogens. In particular, compounds 6g (MIC = 0.031 μg mL-1) and 11b (MIC = 0.016 μg mL-1) were highly active against Candida albicans including fluconazole-resistant strains. Moreover, they showed inhibitory activity against hyphal formation with low toxicity, which were promising leads for further development. This journal is
- He, Xiaomeng,Jiang, Yan,Zhang, Yongqiang,Wu, Shanchao,Dong, Guoqiang,Liu, Na,Liu, Yang,Yao, Jianzhong,Miao, Zhenyuan,Wang, Yan,Zhang, Wannian,Sheng, Chunquan
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p. 653 - 664
(2015/04/27)
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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)
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- 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
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supporting information
p. 892 - 895
(2014/03/21)
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- One-pot synthesis of highly substituted polyheteroaromatic compounds by rhodium(III)-catalyzed multiple C-H activation and annulation
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A new method for the synthesis of highly substituted naphthyridine-based polyheteroaromatic compounds in high yields proceeds through rhodium(III)-catalyzed multiple C-H bond cleavage and C-C and C-N bond formation in a one-pot process. Such highly substituted polyheteroaromatic compounds have attracted much attention because of their unique π-conjugation, which make them suitable materials for organic semiconductors and luminescent materials. Furthermore, a possible mechanism, which involves multiple chelation-assisted ortho C-H activation, alkyne insertion, and reductive elimination, is proposed for this transformation.
- Jayakumar, Jayachandran,Parthasarathy, Kanniyappan,Chen, Yi-Hsiang,Cheng, Chien-Hong,Lee, Tai-Hua,Chuang, Shih-Ching
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supporting information
p. 9889 - 9892,4
(2014/11/08)
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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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- N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators
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A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.
- Packiarajan, Mathivanan,Mazza Ferreira, Christine G.,Hong, Sang-Phyo,White, Andrew D.,Chandrasena, Gamini,Pu, Xiaosui,Brodbeck, Robbin M.,Robichaud, Albert J.
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scheme or table
p. 5658 - 5662
(2012/09/22)
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- Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs
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Here we report the discovery and early SAR of a series of mGluR5 negative allosteric modulators (NAMs). Starting from a moderately active HTS hit we synthesized 3,5-disubstituted-oxadiazoles and tetrazoles as mGluR5 NAMs. Based on the analysis of ligand e
- Wágner, Gábor,Wéber, Csaba,Nyéki, Olga,Nógrádi, Katalin,Bielik, Attila,Molnár, László,Bobok, Amrita,Horváth, Attila,Kiss, Béla,Kolok, Sándor,Nagy, József,Kurkó, Dalma,Gál, Krisztina,Greiner, István,Szombathelyi, Zsolt,Keser, Gy?rgy M.,Domány, Gy?rgy
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scheme or table
p. 3737 - 3741
(2010/08/20)
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- Synthesis, characterization, and antimicrobial activities of clubbed [1,2,4]-oxadiazoles with fluorobenzimidazoles
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(Chemical Equation Presented) In this study, a novel series of substituted 4,6-difluoro-2-{2-[3-(substituted-phenyl)-[1,2,4]-oxadiazol-5-yl]-ethyl} -1H-benzo[d]imidazole derivatives were synthesized by condensation of 2,4-difluoro-6-nitrophenyl amine with 3-(substitutedphenyl-[1,2,4]-oxadiazol- 5yl) propionic acid by using 2,4,6-trichlorobenzoyl chloride in the presence of triethyl amine base. The compounds were evaluated for their preliminary in vitro antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Salmonella typhosa. The antibacterial data of the tested compounds indicated that most of the synthesized compounds showed moderate activity with reference standard Gentamycin.
- Jadhav, Ganesh R.,Shaikh, Mohammad U.,Kale, Rajesh P.,Ghawalkar, Anand R.,Gill, Charansingh H.
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experimental part
p. 980 - 987
(2009/12/05)
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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 111
(2008/06/13)
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- NEW COMPOUNDS
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The present invention relates to new compounds of formula I, (I) a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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- Synthesis of 3,5-disubstituted-1,2,4-oxadiazoles using tetrabutylammonium fluoride as a mild and efficient catalyst
-
Tetrabutylammonium fluoride (TBAF) was found to be a mild and efficient catalyst for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles. Using 0.1 - 1.0 equivalents of TBAF in THF for 1 - 24 h at room temperature, alkanoyl- and aroyloxyamidines were converted in high yield to the corresponding 3,5-disubstituted-1,2,4-oxadiazoles. A variety of R and R′ substituents were investigated.
- Gangloff, Anthony R.,Litvak, Joane,Shelton, Emma J.,Sperandio, David,Wang, Vivian R.,Rice, Kenneth D.
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p. 1441 - 1443
(2007/10/03)
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- An approach to pyrimidine N-oxides: Carboxamide oximes as precursors
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A method for the synthesis of pyrimidines N-oxides is described. Various carboxamide oximes were treated with the appropriate 1,3-dicarbonyl compounds or their equivalents in the presence of trifluoroacetic acid as a catalyst to give the corresponding pyr
- Mlakar, Biserka,?tefane, Bogdan,Ko?evar, Marijan,Polanc, Slovenko
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p. 961 - 973
(2007/10/03)
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- 3,3-Dinitrobutyl-1,2,4-oxadiazoles
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The syntheses of 3,5-bis(3,3-dinitrobutyl)-1,2,4-oxadiazole and a series of 3-aryl-5-(3,3-dinitrobutyl)-1,2,4-oxadiazoles were accomplished by treating 4,4-dinitropentanoyl chloride with the appropriate amidoximes to yield the intermediate O-(4,4-dinitrop
- Bjorklund, Mark D.,Coburn, Michael D.
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p. 819 - 821
(2007/10/02)
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