- Novel O-acylated amidoximes and substituted 1,2,4-oxadiazoles synthesised from (+)-ketopinic acid possessing potent virus-inhibiting activity against phylogenetically distinct influenza A viruses
-
This article describes the synthesis and antiviral activity evaluation of new substituted 1,2,4-oxadiazoles containing a bicyclic substituent at position 5 of the heterocycle and O-acylated amidoximes as precursors for their synthesis. New compounds were
- Borisevich, Sophia S.,Chernyshov, Vladimir V.,Esaulkova, Iana L.,Popadyuk, Irina I.,Salakhutdinov, Nariman F.,Sinegubova, Ekaterina,Yarovaya, Olga I.,Zarubaev, Vladimir V.
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- New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties
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Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu4 receptor positive allosteric modulatory activity (EC50 = 282–656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1, mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in?vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM ADX88178.
- Stankiewicz, Anna,Kaczorowska, Katarzyna,Bugno, Ryszard,Kozio?, Aneta,Paluchowska, Maria H.,Burnat, Grzegorz,Chru?cicka, Barbara,Chorobik, Paulina,Brański, Piotr,Wierońska, Joanna M.,Duszyńska, Beata,Pilc, Andrzej,Bojarski, Andrzej J.
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p. 211 - 225
(2021/12/21)
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- Olefination via Cu-Mediated Dehydroacylation of Unstrained Ketones
-
The dehydroacylation of ketones to olefins is realized under mild conditions, which exhibits a unique reaction pathway involving aromatization-driven C-C cleavage to remove the acyl moiety, followed by Cu-mediated oxidative elimination to form an alkene between the α and β carbons. The newly adopted N′-methylpicolinohydrazonamide (MPHA) reagent is key to enable efficient cleavage of ketone C-C bonds at room temperature. Diverse alkyl- and aryl-substituted olefins, dienes, and special alkenes are generated with broad functional group tolerance. Strategic applications of this method are also demonstrated.
- Dong, Guangbin,Xu, Yan,Zhou, Xukai
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supporting information
p. 20042 - 20048
(2021/12/03)
-
- Imidazole hydrochloride promoted synthesis of 3,5-disubstituted-1,2,4-oxadiazoles
-
Imidazole hydrochloride as an additive promotes the reaction of amidoximes and DMA derivatives to generated 3,5-disubstituted-1,2,4-oxadiazoles in low to excellent yields without the use of coupling reagents, oxidants, strong acids or bases and other additives.
- Wang, Xuetong,Wang, Yin,Liu, Xiaoling,He, Tingshu,Li, Lingli,Wu, Huili,Zhou, Shangjun,Li, Dan,Liao, Siwei,Xu, Ping,Huang, Xing,Yuan, Jianyong
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supporting information
(2021/10/14)
-
- An Efficient Synthesis of 2-Substituted Quinazolin-4(3H)-ones by Using Recyclable Wang Resin Supported Sulfonic Acid Catalyst
-
An efficient synthesis of 2-substituted Quinazolin-4(3H)-ones has been developed from isatoic anhydride with various amidoximes by using a recyclable polymer-supported sulphonic acid catalyst. Excellent functional group compatibility and high yields are the important features of this protocol.
- Kalyani,Kallam, Srinivasa Reddy
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p. 790 - 796
(2022/03/01)
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- SO2F2-Mediated one-pot cascade process for transformation of aldehydes (RCHO) to cyanamides (RNHCN)
-
A simple, mild and practical cascade process for the direct conversion of aldehydes to cyanamides was developed featuring a wide substrate scope and great functional group tolerability. This method allows for transformations of readily available, inexpensive, and abundant aldehydes to highly valuable cyanamides in a pot, atom, and step-economical manner with a green nitrogen source. This protocol will serve as a robust tool for the installation of the cyanamide moiety in various complicated molecules.
- Ding, Chengrong,Ge, Shuting,Wei, Junjie,Zhang, Guofu,Zhao, Yiyong
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p. 17288 - 17292
(2020/05/18)
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- 5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein
-
The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28, showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.
- Malancona, Savina,Mori, Mattia,Fezzardi, Paola,Santoriello, Marisabella,Basta, Andreina,Nibbio, Martina,Kovalenko, Lesia,Speziale, Roberto,Battista, Maria Rosaria,Cellucci, Antonella,Gennari, Nadia,Monteagudo, Edith,Di Marco, Annalise,Giannini, Alessia,Sharma, Rajhans,Pires, Manuel,Real, Eleonore,Zazzi, Maurizio,Dasso Lang, Maria Chiara,De Forni, Davide,Saladini, Francesco,Mely, Yves,Summa, Vincenzo,Harper, Steven,Botta, Maurizio
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supporting information
p. 766 - 772
(2020/07/14)
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- 1,2,4-oxadiazole derivatives as allosteric modulators of metabotropic glutamate receptors belonging to group III
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The present invention relates to the novel 1,2,4-oxadiazole derivatives of general Formula I, wherein A, B, M, X, Y, R 1 , R 2 and R 3 are defined in the application. The compounds of the invention are modulators of metabotropic glutamate receptors that b
- -
-
Paragraph 0063; 0064; 0224; 0225
(2020/12/16)
-
- Design, synthesis and biological activities of piperidine-spirooxadiazole derivatives as α7 nicotinic receptor antagonists
-
α: 7 nicotinic acetylcholine receptors (nAChRs) expressed in the nervous and immune systems have been suggested to play important roles in the control of inflammation. However, the lack of antagonist tools specifically inhibiting α7 nAChR impedes the validation of the channel as therapeutic target. To discover a selective α7 antagonist, we started a pharmacophore-based virtual screening and identified a piperidine-spirooxadiazole derivative T761–0184 that acts as a α7 antagonist. A series of novel piperidine-spirooxadiazole derivatives were subsequently synthesized and evaluated using two-electrode voltage clamp (TEVC) assay in Xenopus oocytes. Lead compounds from two series inhibited α7 with their IC50 values ranging from 3.3 μM to 13.7 μM. Compound B10 exhibited α7 selectivity over other α4β2 and α3β4 nAChR subtypes. The analysis of structure-activity relationship (SAR) provides valuable insights for further development of selective α7 nAChR antagonists.
- Zhang, Han,He, Xiaomeng,Wang, Xintong,Yu, Bo,Zhao, Siqi,Jiao, Peili,Jin, Hongwei,Liu, Zhenming,Wang, KeWei,Zhang, Liangren,Zhang, Lihe
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-
- COMPOUNDS THAT INTERACT WITH THE RAS SUPERFAMILY FOR THE TREATMENT OF CANCERS, INFLAMMATORY DISEASES, RASOPATHIES, AND F1BROTIC DISEASE
-
Provided herein are methods and compositions for treating cancers, inflammatory diseases, rasopathies, and fibrotic disease involving aberrant Ras superfamily signaling through the binding of compounds to the GTP binding domain of Ras superfamily proteins including, in certain cases, K-Ras and mutants thereof, and a method for assaying such compositions.
- -
-
Paragraph 00540
(2020/07/14)
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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
-
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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-
- A cascade process for directly converting nitriles (RCN) to cyanamides (RNHCN) via SO2F2-activated Tiemann rearrangement
-
A simple, mild and practical process for the direct conversion of nitriles to cyanamides was newly discovered and exhibited a wide substrate scope as well as great functional group-tolerability (36 examples). In this efficient strategy, the in situ generated amidoximes obtained from the reaction of nitriles with hydroxylamine subsequently underwent Tiemann rearrangement, producing the corresponding cyanamides with great isolated yields under SO2F2. Additionally, the control experiments reportedly shed light on the tentative mechanism involved in the formation and elimination of the key intermediate: a sulfonyl ester.
- Zhang, Guofu,Zhao, Yiyong,Ding, Chengrong
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supporting information
p. 7684 - 7688
(2019/08/30)
-
- COMPOUNDS AND USES THEREOF
-
The present invention features compounds useful in the treatment of neurological disorders. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders.
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-
Page/Page column 174
(2018/05/17)
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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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- HIV-1 NUCLEOCAPSID INHIBITORS
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The present invention discloses novel anti-HIV agents targeting the HIV Nucleocapsid protein (NC), which is one of the most conserved sequences within HIV strains and is highly required for HIV replication. The compounds of the invention are particularly useful to overcome antiretroviral drug-resistance in HIV-1 infected individuals.
- -
-
Paragraph 0102; 0103; 0104
(2018/04/21)
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- Facile room-temperature assembly of the 1,2,4-oxadiazole core from readily available amidoximes and carboxylic acids
-
A one-pot ambient-temperature procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from amidoximes and carboxylic acids under superbase-promoted conditions is reported.
- Sharonova, Tatyana,Pankrat'eva, Vitalina,Savko, Polyna,Baykov, Sergey,Shetnev, Anton
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supporting information
p. 2824 - 2827
(2018/06/13)
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- An efficient synthesis and antimicrobial evaluation of 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles
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The cyclodehydration of O-acylamidoximes at room temperature in the superbase system KOH/DMSO represents a simple and efficient way to 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles. This method is suitable for the preparation of 5-(4-vinylphenyl)-1,2,4-oxadia
- Tarasenko, Marina,Sidneva, Vera,Belova, Alexandra,Romanycheva, Anna,Sharonova, Tatyana,Baykov, Sergey,Shetnev, Anton,Kofanov, Eugeniy,Kuznetsov, Mikhail A.
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supporting information
p. 458 - 470
(2019/03/07)
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- Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan
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Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure-activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines. In a chemoresistant-RCC cell line, inhibition of miR-21 via small molecule treatment rescued the expression of tumor-suppressor proteins and sensitized cells to topotecan-induced apoptosis. This resulted in a >10-fold improvement in topotecan activity in cell viability and clonogenic assays. Overall, this work reports a novel small molecule inhibitor for perturbing miR-21 function and demonstrates an approach to enhancing the potency of chemotherapeutics specifically for cancers derived from oncomir addiction.
- Naro, Yuta,Ankenbruck, Nicholas,Thomas, Meryl,Tivon, Yaniv,Connelly, Colleen M.,Gardner, Laura,Deiters, Alexander
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p. 5900 - 5909
(2018/08/04)
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- Reactions of pentafluoropyridine with amidoximes
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Abstract: In this paper, site reactivity of amidoximes with pentafluoropyridine under basic conditions in dry CH3CN was investigated. The aromatic nucleophilic substitution of pentafluoropyridine with amidoximes occurs in the 4-position of the
- Ranjbar-Karimi, Reza,Karbakhsh-Ravari, Asma,Poorfreidoni, Alireza
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p. 2397 - 2405
(2017/10/30)
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- ALIPHATIC-AROMATIC HETEROCYCLIC COMPOUNDS AND USES THEREOF IN METAL EXTRACTANT COMPOSITIONS
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The invention relates to an aliphatic-aromatic heterocyclic compound A which comprises at least two heterocyclic rings B and C, to a metal extractant composition E comprising this aliphatic-aromatic heterocyclic compound A and an organic acid D having at least one carboxylic, sulfonic, sulfuric, phosphinic, phosphonic, or phosphoric acid group, and to a process to extract one or more metals M selected from the group consisting of Ni and Co from an aqueous acidic leach solution PL comprising ions of at least one of the metals M, and further, at least one kind of further ions selected from the group consisting of Fe ions, Al ions, Cu ions, Mg ions, Mn ions, and also silicate anions, by mixing the solution PL with an extractant composition E, separating the organic and aqueous phases, and recovering the metal M from the separated organic phase.
- -
-
Paragraph 0144-0145
(2016/09/26)
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- Exploring the readthrough of nonsense mutations by non-acidic Ataluren analogues selected by ligand-based virtual screening
-
Ataluren, also known as PTC124, is a 5-(fluorophenyl)-1,2,4-oxadiazolyl-benzoic acid suggested to suppress nonsense mutations by readthrough of premature stop codons in the mRNA. Potential interaction of PTC124 with mRNA has been recently studied by molec
- Pibiri, Ivana,Lentini, Laura,Tutone, Marco,Melfi, Raffaella,Pace, Andrea,Di Leonardo, Aldo
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p. 429 - 435
(2016/07/15)
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- Expanding Synthesizable Space of Disubstituted 1,2,4-Oxadiazoles
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One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from carboxylic acids and nitriles was optimized to parallel chemistry. The method was validated on a 141 member library; the desired products were recovered with a high success rate and in moderate yields. Practical application of the approach was demonstrated in the synthesis of bioactive compound pifexole and agonists of free fatty acid receptor 1. A library of 4 948 100 synthesizable drug-like 3,5-disubstituted 1,2,4-oxadiazoles was enumerated based on the method and available validated reagents.
- Tolmachev, Andrey,Bogolubsky, Andrey V.,Pipko, Sergey E.,Grishchenko, Alexander V.,Ushakov, Dmytro V.,Zhemera, Anton V.,Viniychuk, Oleksandr O.,Konovets, Anzhelika I.,Zaporozhets, Olga A.,Mykhailiuk, Pavel K.,Moroz, Yurii S.
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p. 616 - 624
(2016/10/21)
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- THERAPEUTIC COMPOUNDS AND USES THEREOF
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The present invention relates to compounds formula (I): and to salts thereof, wherein R1-R4 and A have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of histone demethylases, such as KDM5. Also included are pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.
- -
-
Paragraph 0451; 0452
(2015/03/16)
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- O-Benzoyl pyridine aldoxime and amidoxime derivatives: Novel efficient DNA photo-cleavage agents
-
O-Benzoyl derivatives of meta-, ortho- and para-pyridine aldoximes and amidoximes are novel efficient DNA photo-cleavage agents. In particular O-p-nitro-benzoyl derivatives 4, 8 and 15 were effective at concentrations as low as 1 μM. Both aldoximes and amidoximes were active under aerobic and anaerobic conditions, with a double-stranded to single-stranded DNA cleavage ratio of up to 1. These results give prospects for multiple applications, including phototherapeutic treatment of solid tumors. This journal is
- Karamtzioti, Paraskevi,Papastergiou, Asterios,Stefanakis, John G.,Koumbis, Alexandros E.,Anastasiou, Ioanna,Koffa, Maria,Fylaktakidou, Konstantina C.
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supporting information
p. 719 - 726
(2015/04/27)
-
- Whole cell screen based identification of spiropiperidines with potent antitubercular properties
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Abstract Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[indene-1,4′-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[chromene-2,4′-piperidine] (abbr. spirochromenes) and 1′-benzylspiro[indole-1,4′-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ≥4 log10 kill (at 2-12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.
- Tantry, Subramanyam J.,Degiacomi, Giulia,Sharma, Sreevalli,Jena, Lalit Kumar,Narayan, Ashwini,Guptha, Supreeth,Shanbhag, Gajanan,Menasinakai, Sreenivasaiah,Mallya, Meenakshi,Awasthy, Disha,Balakrishnan, Gayathri,Kaur, Parvinder,Bhattacharjee, Deepa,Narayan, Chandan,Reddy, Jitendar,Naveen Kumar,Shandil, Radha,Boldrin, Francesca,Ventura, Marcello,Manganelli, Riccardo,Hartkoorn, Ruben C.,Cole, Stewart T.,Panda, Manoranjan,Markad, Shankar D.,Ramachandran, Vasanthi,Ghorpade, Sandeep R.,Dinesh, Neela
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p. 3234 - 3245
(2015/07/08)
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- An Efficient Synthesis of 2-Substituted Quinazolin-4(3 H)-ones Catalyzed by Iron(III) Chloride
-
A simple and highly efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the iron(III) chloride catalyzed reaction of isatoic anhydride with various amidoxime derivatives was developed. Several aryl and alkyl amidoximes were screened to demonstra
- Mekala, Ramamohan,Akula, Raghunadh,Kamaraju, Raghavendra Rao,Bannoth, Chandrasekhar Kothapalli,Regati, Sridhar,Sarva, Jayaprakash
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supporting information
p. 821 - 826
(2014/04/03)
-
- An experimental and theoretical study of reaction mechanisms between nitriles and hydroxylamine
-
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)
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- Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors
-
Screening of the 50 000 ChemBridge compound library led to the identification of the oxadiazole-isopropylamide 1 (PI-1833) which inhibited chymotrypsin-like (CT-L) activity (IC50 = 0.60 μM) with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L). LC-MS/MS and dialysis show that 1 is a noncovalent and rapidly reversible CT-L inhibitor. Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 = 27 nM). Detailed SAR studies indicate that the amide moiety and the two phenyl rings are sensitive toward modifications. Hydrophobic residues, such as propyl or butyl in the para position (not ortho or meta) of the A-ring and a m-pyridyl group as B-ring, significantly improve activity. Compound 11ad (IC50 = 0.37 μM) is more potent than 1 (IC50 = 3.5 μM) at inhibiting CT-L activity in intact MDA-MB-468 human breast cancer cells and inhibiting their survival. The activity of 11ad warrants further preclinical investigation of this class as noncovalent proteasome inhibitors.
- Ozcan, Sevil,Kazi, Aslamuzzaman,Marsilio, Frank,Fang, Bin,Guida, Wayne C.,Koomen, John,Lawrence, Harshani R.,Sebti, Sa?d M.
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supporting information
p. 3783 - 3805
(2013/06/27)
-
- COMPOUNDS HAVING AN ETHR INHIBITING ACTIVITY - USE OF SAID COMPOUNDS AS DRUGS - PHARMACEUTICAL COMPOSITION AND PRODUCT CONTAINING SAID COMPOUNDS
-
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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- Unexpected coordination behaviour of 3,5-Di(2-pyridyl)-1,2,4-oxadiazole
-
The coordination behaviour of 3,5-di(2-pyridyl)-1,2,4-oxadiazole (L′) has been studied and compared with that of the 2,5-di(2-pyridyl)-1,3,4- chalcadiazoles LO, LS and LSe [LO = 2,5-di(2-pyridyl)-1,3,4-oxadiazol
- Klingele, Julia,Kaase, Dominic,Schmucker, Maximilian,Meier, Lea
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p. 4931 - 4939
(2013/10/21)
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- Condensation of Vilsmeier salts, derived from tetraalkylureas, with amidoximes: a novel approach to access N,N-dialkyl-1,2,4-oxadiazol-5-amines
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A novel approach, consendation of vilsmeier salts and amidoximes, to access N,N-dialkyl-1,2,4-oxadiazol-5-amines has been developed. By this approach, a broad range of N,N-dialkyl-1,2,4-oxadiazol-5-amines, including aromatic, heteroaromatic and alphatic s
- Su, Dongshan,Duan, Haifeng,Wei, Zhonglin,Cao, Jungang,Liang, Dapeng,Lin, Yingjie
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supporting information
p. 6959 - 6963
(2019/04/10)
-
- PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS
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Focused library synthesis and medicinal chemistry on an oxadiazole- isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring?s para-position and meta-pyridyl group at the B- ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer)
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Page/Page column 68
(2012/10/08)
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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
-
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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- 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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- Discovery and characterization of AZD9272 and AZD6538 - Two novel mGluR5 negative allosteric modulators selected for clinical development
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AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
- Raboisson, Patrick,Breitholtz-Emanuelsson, Anna,Dahlloef, Henrik,Kers, Annika,Minidis, Alexander B. E.,Nordmark, Anna,Stroem, Peter,Terelius, Ylva,Wensbo, David,Edwards, Louise,Isaac, Methvin,Jarvie, Keith,Slassi, Abdelmalik,Wilson, Julie M.,Xin, Tao,Heaton, William L.,Sheehan, Susan M.,McLeod, Donald A.
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p. 6974 - 6979,6
(2020/09/02)
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- Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors
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A microscale chemistry improvement engine: A pre-dosed microscale high-throughput experimentation additives platform enables rapid, serendipitous reaction improvement. This platform allowed one chemist to set up 475 experiments and analyze the results using MISER chromatography in a single day, thus resulting in two high-quality catalytic systems for the construction of the title compound 1. Support for a single-electron transfer mechanism was obtained. Copyright
- Bellomo, Ana,Celebi-Olcum, Nihan,Bu, Xiaodong,Rivera, Nelo,Ruck, Rebecca T.,Welch, Christopher J.,Houk, Kendall N.,Dreher, Spencer D.
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supporting information; body text
p. 6912 - 6915
(2012/10/08)
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- Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl] piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors
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The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
- Ontoria, Jesus M.,Bufi, Laura Llauger,Torrisi, Caterina,Bresciani, Alberto,Giomini, Claudia,Rowley, Michael,Serafini, Sergio,Bin, Hu,Hao, Wu,Steinkühler, Christian,Jones, Philip
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scheme or table
p. 5274 - 5282
(2011/10/02)
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- Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement
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4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity an
- Shen, Hong C.,Ding, Fa-Xiang,Wang, Siyi,Deng, Qiaolin,Zhang, Xiaoping,Chen, Yuli,Zhou, Gaochao,Xu, Suoyu,Chen, Hsuan-Shen,Tong, Xinchun,Tong, Vincent,Mitra, Kaushik,Kumar, Sanjeev,Tsai, Christine,Stevenson, Andra S.,Pai, Lee-Yuh,Alonso-Galicia, Magdalena,Chen, Xiaoli,Soisson, Stephen M.,Roy, Sophie,Zhang, Bei,Tata, James R.,Berger, Joel P.,Colletti, Steven L.
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supporting information; experimental part
p. 5009 - 5012
(2010/03/02)
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- Novel macrolides and ketolides having antimicrobial activity
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The present invention provides compounds having antimicrobial activity for preventing and treating diseases caused by microbial infections. Thus, the present invention relates to novel semi-synthetic 11,12-γ lactone macrolides and ketolides having antimicrobial activity, processes for making compounds as well as pharmaceutical compositions containing said compounds as active ingredients and methods of treating microbial infections with the compounds.
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Page/Page column 46
(2009/10/06)
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- Synthesis and antibacterial activity of novel pyridine and pyrazine derivatives obtained from amidoximes
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(Chemical Equation Presented) The new pyridine, 4-pyridine N-oxide and pyrazine derivatives exhibiting an antibacterial activity have been synthesized. Amidoximes were transformed into N-hydroxyimidoyl chlorides and then into appropriate oximes. Upon treatment of pyridinecaboxamidoximes with methyl iodide 1-methylpyridynium iodides were formed. Reaction of amidoximes with various carbamoyl chlorides led to corresponding 5-aminocarbonyl-1,2,4-oxadiazoles. Some of carboxamides have undergone thermal decarboxylation to tertiary amines. The newly synthesized compounds were tested in vitro for their tuberculostatic activity. MIC of the most active compound 9 was 12.5 μg/mL for H 37Rv strain. Their activity towards 25 strains of anaerobic and 25 strains of aerobic bacteria was also studied. Derivative 18 was active against both aerobic and anaerobic types of the bacteria.
- Gobis, Katarzyna,Foks, Henryk,Kedzia, Anna,Wierzbowska, Maria,Zwolska, Zofia
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experimental part
p. 1271 - 1279
(2010/03/23)
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- NOVEL MACROLIDES AND KETOLIDES HAVING ANTIMICROBIAL ACTIVITY
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The present invention provides compounds having antimicrobial activity for preventing and treating diseases caused by microbial infections. Thus, the present invention relates to novel ? semi-synthetic 11,12-γ lactone macrolides and ketolides having antimicrobial activity, processes for making compounds as well as pharmaceutical compositions containing said compounds as active ingredients and methods of treating microbial infections with the compounds.
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Page/Page column 87
(2008/06/13)
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- Rapid multistep synthesis of 1,2,4-oxadiazoles in a single continuous microreactor sequence
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(Chemical Equation Presented) A general method for the synthesis of bis-substituted 1,2,4-oxadiazoles from readily available arylnitriles and activated carbonyls in a single continuous microreactor sequence is described. The synthesis incorporates three s
- Grant, Daniel,Dahl, Russell,Cosford, Nicholas D. P.
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experimental part
p. 7219 - 7223
(2009/05/07)
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- Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors
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Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine- 4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
- Pace, Paola,Di Francesco, M. Emilia,Gardelli, Cristina,Harper, Steven,Muraglia, Ester,Nizi, Emanuela,Orvieto, Federica,Petrocchi, Alessia,Poma, Marco,Rowley, Michael,Scarpelli, Rita,Laufer, Ralph,Paz, Odalys Gonzalez,Monteagudo, Edith,Bonelli, Fabio,Hazuda, Daria,Stillmock, Kara A.,Summa, Vincenzo
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p. 2225 - 2239
(2007/10/03)
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- Potent and selective nonpeptidic inhibitors of procollagen C-proteinase
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6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 ± 2% at 10 μM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 μg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.
- Fish, Paul V.,Allan, Gillian A.,Bailey, Simon,Blagg, Julian,Butt, Richard,Collis, Michael G.,Greiling, Doris,James, Kim,Kendall, Jackie,McElroy, Andrew,McCleverty, Dawn,Reed, Charlotte,Webster, Robert,Whitlock, Gavin A.
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p. 3442 - 3456
(2008/02/11)
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- HETEROCYCLIC COMPOUNDS USEFUL AS DPP- IV INHIBITORS
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The invention relates to compounds of formula Z-C(R1R2)-C(R3NH2)-C(R4R5)-A (I) wherein Z, R1-R5 and A have the meaning as cited in the description and the claims as examplified by the compound (II) said compounds are useful as DPP-IV inhibitors. The invention also relates to the preparation of such compounds as well as the production and use thereof as medicament.
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Page/Page column 27
(2010/10/19)
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- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
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The invention relates to compounds of the formula (I) and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula (I), and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula (I). The invention also relates to methods of preparing the compounds of formula (I).
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- Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
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The present invention provides compounds and pharmaceutical compositions that act as antagonists at metabotropic glutamate receptors, and that are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.
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- Substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof
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The present invention is directed to substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs thereof, represented by the Formula I: wherein Ar1, Ar3, A, B and D are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
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- Liquid crystalline pyridine containing 1,2,4-oxadiazoles
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New mesomorphic 1,2,4-oxadiazoles containing as an electron-acceptor substituent the pyridine cycle with different position of the nitrogen atom with respect to the oxadiazole cycle have been synthesized. The reaction of the isonicotinic and nicotinic ami
- Karamysheva, Ludmila A.,Agafonova, Irina F.,Torgova, Sofia I.,Umanskii, Boris A.,Strigazzi, Alfredo
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p. 547 - 556
(2007/10/03)
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