cas 19227-11-3, (1E)-N'-HYDROXY-2-PHENYLETHANIMIDAMIDE

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Discovery and Structure-Activity-Relationship Study of N-Alkyl-5-hydroxypyrimidinone Carboxamides as Novel Antitubercular Agents Targeting Decaprenylphosphoryl-β-D-ribose 2′-Oxidase
Magnesium plays an important role in infection with Mycobacterium tuberculosis (Mtb) as a signal of the extracellular environment, as a cofactor for many enzymes, and as a structural element in important macromolecules. Raltegravir, an antiretroviral drug
Oh, Sangmi,Park, Yumi,Engelhart, Curtis A.,Wallach, Joshua B.,Schnappinger, Dirk,Arora, Kriti,Manikkam, Michelle,Gac, Brian,Wang, Hongwu,Murgolo, Nicholas,Olsen, David B.,Goodwin, Michael,Sutphin, Michelle,Weiner, Danielle M.,Via, Laura E.,Boshoff, Helena I. M.,Barry, Clifton E.
p. 9952 - 9965
(2018)
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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
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
p. 55 - 63
(2019)
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Compositions and Methods for the Treatment of Amyotrophic Lateral Sclerosis, Parkinson's Disease, Parkinson's Disease with Dementia, Dementia with Lewy Bodies, and Multiple System Atrophy
The present disclosure provides novel methods for treating or preventing amyotrophic lateral sclerosis (ALS), methods for delaying the onset of neurological symptoms associated with ALS, increasing survival in subjects afflicted with ALS, and attenuating
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Paragraph 0173-0174

(2021/01/29)

Beyond direct Nrf2 activation; reinvestigating 1,2,4-oxadiazole scaffold as a master key unlocking the antioxidant cellular machinery for cancer therapy
Harnessing the antioxidant cellular machinery has sparked considerable interest as an efficient anticancer strategy. Activating Nrf2, the master switch of the cellular redox system, suppresses ROS, alleviates oxidative stress, and halts cancer progression
Ayoup, Mohammed Salah,Abu-Serie, Marwa M.,Abdel-Hamid, Hamida,Teleb, Mohamed
(2021/04/27)

Synergism of a novel 1,2,4-oxadiazole-containing derivative with oxacillin against methicillin-resistant staphylococcus aureus
Staphylococcus aureus is an important opportunistic pathogen that causes many infections in humans and animals. The inappropriate use of antibiotics has favored the diffusion of methicillin-resistant S. aureus (MRSA), nullifying the efforts undertaken in
Buommino, Elisabetta,D’auria, Maria Valeria,De Marino, Simona,Festa, Carmen,Piccolo, Marialuisa,Sciarretta, Martina
(2021/11/01)

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
p. 17288 - 17292
(2020/05/18)

Synthesis of 2,4-Disubstituted Imidazoles via Nucleophilic Catalysis
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.
supporting information
p. 797 - 800
(2020/05/19)

Novel phthalide derivatives: Synthesis and anti-inflammatory activity in vitro and in vivo
Phthalide is a promising chemical scaffold and has been proved to show potent anti-inflammatory efficacy. In this study, three series, total of 31 novel phthalide derivatives were designed and synthesized, their anti-inflammatory activities were screened
Chen, Liu Zeng,Wu, Jing,Li, Kang,Wu, Qian Qian,Chen, Rui,Liu, Xin Hua,Ruan, Ban Feng
(2020/08/21)

MITOCHONDRIA-TARGETING PEPTIDES
Disclosed are non-natural peptides useful for the treatment and prevention of ischemia-reperfusion injury (e.g., cardiac ischemia-reperfusion injury) or myocardial infarction.
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(2019/07/19)

Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists
Recent findings have shown that Farnesoid X Receptor (FXR) antagonists might be useful in the treatment of cholestasis and related metabolic disorders. In this paper, we report the discovery of a new chemotype of FXR antagonists featured by a 3,5-disubsti
Festa, Carmen,Finamore, Claudia,Marchianò, Silvia,Di Leva, Francesco Saverio,Carino, Adriana,Monti, Maria Chiara,Del Gaudio, Federica,Ceccacci, Sara,Limongelli, Vittorio,Zampella, Angela,Fiorucci, Stefano,De Marino, Simona
supporting information
p. 504 - 510
(2019/01/26)

Discovery of BR102375, a new class of non-TZD PPARγ full agonist for the treatment of type 2 diabetes
As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioisosteres approach. In vitro assessments
Choung, Wonken,Yang, Deokmo,Kim,Choi, Hyukjoon,Lee, Bo Ram,Park, Min,Jang, Su Min,Lim, Jae Soo,Kim, Woo Sik,Kim, Kyung-Hee,Chin, Jungwook,Jung, Kyungjin,Lee, Geumwoo,Hong,Jang, Tae-ho,Joo, Jeongmin,Hwang, Hayoung,Myung, Jayhyuk,Kim, Seong Heon
p. 2275 - 2282
(2019/06/27)

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
supporting information
p. 7684 - 7688
(2019/08/30)

Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator
To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH) group at the 2nd position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth and skeleton muscles.
Manickam, Manoj,Boggu, Pulla Reddy,Pillaiyar, Thanigaimalai,Sharma, Niti,Jalani, Hitesh B.,Venkateswararao, Eeda,Jung, Sang-Hun
supporting information
p. 2369 - 2374
(2018/06/25)

Survey Reactivity of Some Substituted Quinazolinones with Pentafluoro(chloro)pyridine
A new series of 4-hetroaryl substituted quinazolines were designed and synthesized by the reaction of pentafluoro(chloro)pyridine and 2-substituted quinazolinone. The aromatic nucleophilic substitution of pentafluoro(chloro)pyridine with quinazolinone occurs at the 4-position of pyridine ring by the oxygen site (O-centered nucleophile) of quinazolinone. The structures of all the compounds were confirmed by IR, 1H NMR, 19F NMR, and 13C NMR spectroscopy as well as elemental analysis.
Ranjbar-Karimi, Reza,Davodian, Tayebeh,Mehrabi, Hossein
p. 475 - 480
(2017/12/28)

HETEROARYLBENZIMIDAZOLE COMPOUNDS
The present invention covers heteroarylbenzimidazole compounds of general formula (I) in which R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative and/or inflammatory disorders, as a sole agent or in combination with other active ingredients.
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(2017/07/06)

Reactions of pentafluoropyridine with amidoximes
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
p. 2397 - 2405
(2017/10/30)

Indazole-oxadiazole derivative, medicinal composition containing derivative, and application of derivative in tumor prevention
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.
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Paragraph 0099; 0100; 0113; 0114

(2017/07/25)

Synthesis and multiparametric evaluation of thiadiazoles and oxadiazoles as diacylglycerol acyltransferase type 1 inhibitors
Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.
Mougenot, Patrick,Namane, Claudie,Fett, Eykmar,Goumy, Florence,Dadji-Fa?hun, Rommel,Langot, Gwladys,Monseau, Catherine,Onofri, Bénédicte,Pacquet, Fran?ois,Pascal, Cécile,Crespin, Olivier,Ben-Hassine, Majdi,Ragot, Jean-Luc,Van-Pham, Thao,Philippo, Christophe,Chatelain-Egger, Florence,Péron, Philippe,Le Bail, Jean-Christophe,Guillot, Etienne,Chamiot-Clerc, Philippe,Chabanaud, Marie-Aude,Pruniaux, Marie-Pierre,Ménegotto, Jér?me,Schmidt, Friedemann,Venier, Olivier,Viviani, Fabrice,Nicolai, Eric
p. 25 - 32
(2015/12/18)

Nitrobenzofurazan derivatives of N′-hydroxyamidines as potent inhibitors of indoleamine-2,3-dioxygenase 1
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
p. 364 - 375
(2016/06/13)

Novel potent HIF-1 inhibitors for the prevention of tumor metastasis: discovery and optimization of 3-aryl-5-indazole-1,2,4-oxadiazole derivatives
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
p. 81817 - 81830
(2015/10/12)

OXADIAZOLE COMPOUNDS
The present invention relates to a compound of formula (I) or (II) or a stereoisomer, enantiomer, racemic, or tautomer thereof, (I) (II) wherein R1,R2,R3,L1,L2,L3,L4,L5 and n, have the same meaning as that defined in the claims and the description. The present invention also relates to compositions, in particular pharmaceuticals, comprising such compounds, and to uses of such compounds and compositions for the prevention and/or treatment of metabolic disorders and/or neurodegenerative diseases, and/or protein misfolding disorders.
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(2015/11/11)

Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors
A series of novel β-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of DKA and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and
Wang, Yujie,Rong, Jie,Zhang, Bin,Hu, Liming,Wang, Xiaoli,Zeng, Chengchu
p. 735 - 741
(2015/02/19)

One-Pot Synthesis of N-Monosubstituted Ureas from Nitriles via Tiemann Rearrangement
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
supporting information
p. 1823 - 1826
(2015/08/06)

Practical synthesis of N -substituted cyanamides via tiemann rearrangement of amidoximes
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)

Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP)
N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3, 5-trimethyl-1H-pyrazol-4-yl)meth
Rackham, Mark D.,Brannigan, James A.,Rangachari, Kaveri,Meister, Stephan,Wilkinson, Anthony J.,Holder, Anthony A.,Leatherbarrow, Robin J.,Tate, Edward W.
p. 2773 - 2788
(2014/04/17)

Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype
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.
p. 4477 - 4481
(2015/02/19)

Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides
A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia - with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb% = 61.0 ± 3.6) and 1,3,4-oxadiazole 10 (metHb% = 52.4 ± 0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120 mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.
Conole, Daniel,Beck, Thorsten M.,Jay-Smith, Morgan,Tingle, Malcolm D.,Eason, Charles T.,Brimble, Margaret A.,Rennison, David
supporting information
p. 2220 - 2235
(2014/04/17)

DERIVATIVES OF OXADIAZOLE AND PYRIDAZINE, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS
The invention relates to compounds of formula (I): in which: n is equal to 0 or 1; D represents an oxygen atom or a bond; W represents a nitrogen atom or a —CH— group; X1 represents a nitrogen atom or a —CH═CH— group; X2 represents an oxygen atom or a nitrogen atom; X3 represents an oxygen atom or a nitrogen atom; one of X1, X2, X3 being other than a nitrogen atom, X2 and X3 not being an oxygen atom at the same time; R1, R2 are absent or represent, (i) independently of one another, a hydrogen atom or a (C1-C4)alkyl group, (ii) R1 and R2 may form, with the carbon atom to which they are attached, a —(C3-C10)cycloalkyl- group; Y represents a —(C3-C10)cycloalkyl-, aryl or aryloxy group, said groups being optionally substituted with one or more substituents chosen from a halogen atom or a (C1-C6)alkoxy group; Z1 is absent or represents an —NH— function; Z2 and Z3 are as defined in the description. The invention also relates to a process for preparing compounds of formula (I), compositions containing them and their application in therapeutics.
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Paragraph 0351

(2013/06/05)

Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings
A series of anthranilic diamides analogs (3-11, 16-24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by 1H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1, 2,4-oxadiazol-5-yl)-
Li, Yuhao,Zhu, Hongjun,Chen, Kai,Liu, Rui,Khallaf, Abdalla,Zhang, Xiangning,Ni, Jueping
supporting information
p. 3979 - 3988
(2013/07/05)

Clean one-pot synthesis of 1,2,4-oxadiazoles under solvent-free conditions using microwave irradiation and potassium fluoride as catalyst and solid support
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
experimental part
p. 494 - 497
(2010/03/03)

Coordination chemistry based approach to lipophilic inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase
1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-negative bacteria. A coordination chemistry and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC50 of 1.4 μM. It exhibited a broad spectrum of activity against Gram-negative and -positive bacteria with minimal inhibition concentrations of 20-100 μM (or 3.7-19 μg/mL).
Deng, Lisheng,Sundriyal, Sandeep,Rubio, Valentina,Shi, Zheng-Zheng,Song, Yongcheng
supporting information; experimental part
p. 6539 - 6542
(2010/04/04)

STABILIZATION OF HYDROXYLAMINE CONTAINING SOLUTIONS AND METHOD FOR THEIR PREPARATION
The invention relates to the use of amidoximes for prevention of or stabilization of hydroxylamine compounds against undesired decomposition.
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(2009/05/28)

RNase H active site inhibitors of human immunodeficiency virus type 1 reverse transcriptase: Design, biochemical activity, and structural information
Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antivira
Kirschberg, Thorsten A.,Balakrishnan, Mini,Squires, Neil H.,Barnes, Tiffany,Brendza, Katherine M.,Chen, Xiaowu,Eisenberg, Eugene J.,Jin, Weili,Kutty, Nilima,Leavitt, Stephanie,Liclican, Albert,Liu, Qi,Liu, Xiaohong,Mak, John,Perry, Jason K.,Wang, Michael,Watkins, William J.,Lansdon, Eric B.
supporting information; experimental part
p. 5781 - 5784
(2010/03/24)

Acetic acid aldose reductase inhibitors bearing a five-membered heterocyclic core with potent topical activity in a visual impairment rat model
A number of 1,2,4-oxadiazol-5-yl-acetic acids and oxazol-4-yl-acetic acids were synthesized and tested for their ability to inhibit aldose reductase (ALR2). The oxadiazole derivatives, 7c, 7f, 7i, and 8h, 8i, proved to be the most active compounds, exhibiting inhibitory levels in the submicromolar range. In this series, the phenyl group turned out to be the preferred substitution pattern, as its lengthening to a benzyl moiety determined a general reduction of the inhibitory potency. The lead compound, 2-[3-(4-methoxyphenyl)-1,2,4- oxadiazol-5-yl]acetic acid, 7c, showed an excellent in vivo activity, proving to prevent cataract development in severely galactosemic rats when administered as an eye-drop solution in the precorneal region of the animals. Computational studies on the ALR2 inhibitors were performed to rationalize the structure-activity relationships observed and to provide the basis for further structure-guided design of novel ALR2 inhibitors.
La Motta, Concettina,Sartini, Stefania,Salerno, Silvia,Simorini, Francesca,Taliani, Sabrina,Marini, Anna Maria,Da Settimo, Federico,Marinelli, Luciana,Limongelli, Vittorio,Novellino, Ettore
supporting information; experimental part
p. 3182 - 3193
(2009/04/06)

Synthesis and cannabinoid activity of 1-substituted-indole-3-oxadiazole derivatives: Novel agonists for the CB1 receptor
An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB1 agonists. It is hoped that compounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of a series of 1-substituted-indole-3-oxadiazoles as potential CB1 agonists. Crown Copyright
Moloney, Gerard P.,Angus, James A.,Robertson, Alan D.,Stoermer, Martin J.,Robinson, Michael,Wright, Christine E.,McRae, Ken,Christopoulos, Arthur
p. 513 - 539
(2008/12/21)

Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors
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
p. 2225 - 2239
(2007/10/03)

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: Discovery, SAR, modeling, and mutagenesis
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2- thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 μM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.
Koch, Uwe,Attenni, Barbara,Malancona, Savina,Colarusso, Stefania,Conte, Immacolata,Di Filippo, Marcello,Harper, Steven,Pacini, Barbara,Giomini, Claudia,Thomas, Steven,Incitti, Ilario,Tomei, Licia,De Francesco, Raffaele,Altamura, Sergio,Matassa, Victor G.,Narjes, Frank
p. 1693 - 1705
(2007/10/03)

1,3-DISUBSTITUTED HETEROARYL NMDA/NR2B ANTAGONISTS
Compounds represented by Formula I: (wherein A, B, D, P, Q, R1, R2, R3, W and Y are described herein) or pharmaceutically acceptable salts thereof, are effective as NMDA/NR2B antagonists useful for treating neurological co
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Page/Page column 47-48

(2010/10/20)

NOVEL ALKYNYL DERIVATIVES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
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 95-96

(2008/06/13)

NOVEL COMPOUNDS AS AGONIST FOR PPAR GAMMA AND PPAR ALPHA, METHOD FOR PREPARATION OF THE SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
The present invention relates to novel compounds accelerating the activity of Peroxisome proliferator-activated receptor gamma (PPARγ) and alpha (PPARα), processes of preparing the same, and pharmaceutical compositions containing the same as an active agent.
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Page/Page column 158-159

(2010/02/11)

Phosphonic acid derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B)
The invention encompasses the novel class of compounds represented by formula I, which are inhibitors of the PTP-1B enzyme. The invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP-1B mediated diseases, including diabetes, obesity, and conditions related to diabetes.
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(2008/06/13)

Modification of the Tiemann rearrangement: One-pot synthesis of N,N-disubstituted cyanamides from amidoximes
A three-stage one-pot synthetic procedure for transformation of amidoximes to N,N-disubstituted cyanamides in 70-92% yield is described.
Bakunov, Stanislav A.,Rukavishnikov, Alexey V.,Tkachev, Alexey V.
p. 1148 - 1159
(2007/10/03)

Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70
A series of 1,2,4-oxadiazole analogues has been shown to be potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70, a potential therapeutic target for immune suppression. These compounds typically are 200- 400-fold more potent than the native,
Vu, Chi B.,Corpuz, Evelyn G.,Merry, Taylor J.,Pradeepan, Selvaluxmi G.,Bartlett, Catherine,Bohacek, Regine S.,Botfield, Martyn C.,Eyermann, Charles J.,Lynch, Berkley A.,MacNeil, Ian A.,Ram, Mary K.,Van Schravendijk, Marie Rose,Violette, Shelia,Sawyer, Tomi K.
p. 4088 - 4098
(2007/10/03)

Synthesis and serotonergic activity of 2-oxadiazolyl-5-substituted-N,N-dimethyltryptamines: Novel antagonists for the vascular 5-HT1B-like receptor
The synthesis and vascular 5-HT1B-like receptor activity of a novel series of 2-oxadiazolyl-5-substituted tryptamine derivatives 2 is described. Modifications to the 2-oxadiazolyl group R1, the heterocycle R2 and the lengt
Moloney, Gerard P.,Martin, Graeme R.,Mathews, Neil,MacLennan, Steve,Dodsworth, Susan,Sang, Pang Yih,Knight, Cameron,Maxwell, Miles,Glen, Robert C.
p. 2725 - 2733
(2007/10/03)

THE PHOTOELIMINATION OF N-NITROSO-N-ACETYL-α-AMINO-ACIDS; A NEW SYNTHESIS OF 1,2,4-OXADIAZOLES
The excitation of N-nitroso-N-acetyl-α-aminoacids, nitrosopeptide model compounds, under neutral and weakly basic conditions, caused the homolysis of the N-N bond followed by decarboxylation to give hyponitrous acid (HNO) and N-acetylimines which were susceptible to nucleophilic addition.While weak bases caused the carboxylate group to assist intramolecular rearrangement to a small extent, they functioned primarily to provide nucleophilic NO-, which initiated nucleophilic attack leading to the C-nitroso derivatives.These C-nitroso derivatives spontaneously cyclized to 1,2,4-oxadiazoles much more rapidly than tautomerism to the corresponding oximes; the latter oximes failed to cyclize under the basic conditions.
Chow, Yuan L.,Polo, Joel S.
p. 727 - 734
(2007/10/02)

Nonquaternary cholinesterase reactivators. 3. 3(5)-substituted 1,2,4-oxadiazol-5(3)-aldoximes and 1,2,4-oxadiazole-5(3)-thiocarbohydroximates as reactivators of organophosphonate-inhibited eel and human acetylcholinesterase in vitro
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Bedford,Howd,Dailey,Miller,Nolen III,Kenley,Kern,Winterle
p. 2174 - 2183
(2007/10/02)

New Acetonylsubstituted Azoles, I. 5-Acetonyl-1,2,4-oxadiazoles
Aliphatic amidoximes R-C(NH2)=NOH react with diketene to yield 5-acetonyl-3-alkyl-1,2,4-oxadiazoles, which are susceptible to a wide variety of reactions at the keto-group as well as at the methylene-group.Their transformations into 1-methyl-2-oxadiazolyl
Kuebel, Boerries
p. 781 - 792
(2007/10/02)

Insecticidal compositions containing 1,2,4-oxadiazole and thiadiazole esters
Novel 1,2,4-oxadiazole and thiadiazole esters and compositions containing same are described. The esters are useful as insecticides.
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(2008/06/13)