- Copper(ii) ions supported on functionalized graphene oxide: an organometallic nanocatalyst for oxidative amination of azolesviaC-H/C-N bond activation
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Graphene oxide (GO) was chemically modified withpara-aminobenzoic acid (PABA) to immobilize copper(ii) ions on its surface and used as a nanocatalyst for the oxidative C(sp2)-H bond amination reaction. A practical method to prepare Cu2+supported onpara-aminobenzoic acid grafted on GO was reported. The prepared Cu2+@GO/PABA was characterized by FT-IR, XRD, SEM, AFM, TEM, UV-Vis, and ICP techniques. The results showed that the morphology, distribution, and loading of copper ions could be well-adjusted by grafting of PABA on GO. Moreover, just 2 mol% of Cu2+@GO-PABA could catalyze the C-H activation reaction of benzoxazole and benzothiazole with secondary amines in >94% yields. Also, the catalyst showed very good recyclability and much less leaching of the Cu into the reaction solution. The high activity of Cu2+@GO-PABA can be ascribed to the good synergistic effects of Cu2+andpara-aminobenzoic acid grafted on graphene oxide.
- Behzadi, Masoumeh,Mahmoodi Hashemi, Mohammad,Roknizadeh, Mostafa,Nasiri, Shahrokh,Ramazani Saadatabadi, Ahmad
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Read Online
- Synthesis of aminobenzoxazoles via simple, clean and efficient electrochemical redox reactions
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An efficient single step process for the construction of pharmaceutically relevant substituted aminobenzoxazoles have been described in this report. Various electrodes and electrolytes combinations have been carried out to harvest optimum coupling results. The presented C–N bond formation reaction methodology has applied for the synthesis of biologically active compounds. This methodology saves reaction steps over traditional functionalization reactions.
- Ghoshal, Tanay,Nagar, Vishal,Vutla, Adilakshmi,Kotturi, Sharadsrikar,Kuttappan, Sasikumar
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Read Online
- Development of a Practical Process for the Synthesis of PDE4 Inhibitors
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A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inhibitors represented by 1 and 2 was developed and demonstrated on a multi-kilogram scale. Key aspects of the process include the regioselective synthesis of dihydrothieno[3,2-d]pyrimidine-2,4-diol 9 and the asymmetric sulfur oxidation of intermediate 11.
- Frutos, Rogelio P.,Tampone, Thomas G.,Mulder, Jason A.,Rodriguez, Sonia,Yee, Nathan K.,Yang, Bing-Shiou,Senanayake, Chris H.
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Read Online
- Orally active benzoxazole derivative as 5-HT3 receptor partial agonist for treatment of diarrhea-predominant irritable bowel syndrome
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During our search for therapeutic agents to treat diarrhea-predominant IBS, we found that 2-substituted benzoxazole derivatives have a characteristic 5-HT3 receptor partial agonist activity with high affinity. Some of these compounds showed high in vitro metabolical stability, and 6g showed marked antidiarrhetic activity with little side effect of constipation in in vivo tests. Our results indicate that 5-HT3 receptor partial agonists might be superior as therapeutic agents to the drugs currently used for IBS treatment.
- Yoshida, Satoshi,Shiokawa, Sojiro,Kawano, Ken-Ichi,Ito, Tomoko,Murakami, Hiroshi,Suzuki, Hisashi,Sato, Yasuo
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Read Online
- Selective targeting of the αC and DFG-out pocket in p38 MAPK
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The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.
- R?hm, Sandra,Schr?der, Martin,Dwyer, Jessica E.,Widdowson, Caroline S.,Chaikuad, Apirat,Berger, Benedict-Tilman,Joerger, Andreas C.,Kr?mer, Andreas,Harbig, Jule,Dauch, Daniel,Kudolo, Mark,Laufer, Stefan,Bagley, Mark C.,Knapp, Stefan
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- Small-compound enhancers for functional O-mannosylation of alpha-dystroglycan, and uses thereof
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The present invention provides compounds that can enhance functional O-mannosylation of proteins including alpha-dystroglycan. Also provided are methods of preparation of the compounds defined by the formula I. Also provided are the methods of using the compounds or the pharmaceutical acceptable salts or prodrugs thereof in treating and preventing subjects suffering from the diseases including muscular dystrophies and cancers.
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Page/Page column 26; 37
(2019/03/14)
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- Pd-Catalyzed Synthesis of Piperazine Scaffolds under Aerobic and Solvent-Free Conditions
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A facile Pd-catalyzed methodology providing an efficient synthetic route to biologically relevant arylpiperazines under aerobic conditions is reported. Electron donating and sterically hindered aryl chlorides were aminated to afford yields up to 97%, with examples using piperazine as solvent, illustrating an ecofriendly, cost-effective synthesis of these privileged structures.
- Reilly, Sean W.,Mach, Robert H.
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supporting information
p. 5272 - 5275
(2016/10/31)
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- 2-Benzazolyl-4-Piperazin-1- Ylsulfonylbenzenecarbohydroxamic acids as novel selective histone deacetylase-6 inhibitors with antiproliferative activity
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We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-yl)piperazin-1- yl]sulfonylbenzenecarbohydroxamic acid (9b) as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d) were active HDAC inhibitors, the meta substituted analogues (8a-d) were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1-1.0μM) over HDAC1 (IC50 = 0.9-6μM) and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MMGBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity.
- Wang, Lei,Kofler, Marina,Brosch, Gerald,Melesina, Jelena,Sippl, Wolfgang,Martinez, Elisabeth D.,Easmon, Johnny
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- Small molecules enhance functional O-mannosylation of Alpha-dystroglycan
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Alpha-dystroglycan (α-DG), a highly glycosylated receptor for extracellular matrix proteins, plays a critical role in many biological processes. Hypoglycosylation of α-DG results in various types of muscular dystrophies and is also highly associated with progression of majority of cancers. Currently, there are no effective treatments for those devastating diseases. Enhancing functional O-mannosyl glycans (FOG) of α-DG on the cell surfaces is a potential approach to address this unmet challenge. Based on the hypothesis that the cells can up-regulate FOG of α-DG in response to certain chemical stimuli, we developed a cell-based high-throughput screening (HTS) platform for searching chemical enhancers of FOG of α-DG from a large chemical library with 364,168 compounds. Sequential validation of the hits from a primary screening campaign and chemical works led to identification of a cluster of compounds that positively modulate FOG of α-DG on various cell surfaces including patient-derived myoblasts. These compounds enhance FOG of α-DG by almost ten folds, which provide us powerful tools for O-mannosylation studies and potential starting points for the development of drug to treat dystroglycanopathy.
- Lv, Fengping,Li, Zhi-Fang,Hu, Wenhao,Wu, Xiaohua
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p. 7661 - 7670
(2015/12/18)
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- GLUCAN SYNTHASE INHIBITORS
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The present invention provides compounds with anti-fungal activity useful for treatment or prevention of fungal infections in human beings or plants. The antifungal compounds are inhibitors of glucan synthase and have the formula (I) (I) wherein Z denotes
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Page/Page column 33
(2014/08/20)
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- Synthesis and biological analysis of benzazol-2-yl piperazine sulfonamides as 11β-hydroxysteroid dehydrogenase 1 inhibitors
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In the last decade the inhibition of the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) emerged as a promising new strategy to treat diabetes and several metabolic syndrome phenotypes. Using a molecular modeling approach and classical bioisosteric studies, we discovered a new class of 11β-HSD1 inhibitors bearing an arylsulfonylpiperazine scaffold. Optimization of the initial lead resulted in compound 11 that selectively inhibits 11β-HSD1 (IC50 = 0.7 μM).
- Hofer, Sandra,Kratschmar, Denise V.,Schernthanner, Brigitte,Vuorinen, Anna,Schuster, Daniela,Odermatt, Alex,Easmon, Johnny
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supporting information
p. 5397 - 5400
(2013/09/23)
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- Synthesis of piperazinyl benzothiazole/benzoxazole derivatives coupled with 1,3,4-oxadiazole-2-thiol: Novel hybrid heterocycles as anticancer agents
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The synthesis of a series of substituted 2-(piperazin-1-yl)benzothiazole/ benzoxazole coupled with 1,3,4-oxadiazole-2-thiol pharmacophore (8a-t) is described using a three carbon spacer (Jones and Helm, Drugs 69:1903-1910, 2009). The structures of the compounds were confirmed by NMR and mass spectral data. All the synthesized compounds have been evaluated for their cytotoxicity towards five human cancer cell lines of different origins, viz. MCF-7 (Breast), HeLa (Cervical), HepG2 (Liver), A431 (Skin) and A549 (Lung), and IC50 values were determined. Among the compounds tested, 8j and 8t displayed maximum cytotoxic activity. A431 was the most sensitive cell line against the compounds studied, followed by MCF7, A549, HepG2 and HeLa.
- Murty,Ramalingeswara Rao,Katiki, Mohana Rao,Nath, Lekshmi R.,Anto, Ruby John
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p. 4980 - 4991
(2013/09/23)
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- DRUG COMBINATIONS CONTAINING PDE4 INHIBITORS AND NSAIDS
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The present invention relates to new drug combinations which contain in addition to one or more PDE4-inhibitors at least one NSAID (=non-steroidal anti-inflammatory drug) (2), processes for preparing them and their use in treating in particular respiratory complaints such as for example COPD, chronic sinusitis and asthma. The invention particularly relates to those drug combinations which, in addition to one or more, preferably one PDE4 inhibitor of general formula 1 wherein X is SO or SO2, but preferably SO, and wherein R3 denotes an optionally substituted, mono- or bicyclic, unsaturated, partly saturated or saturated heterocyclic group or an optionally substituted, mono- or bicyclic heteroaryl and wherein R1 and R2 have the meanings given in claim 1, contain at least one NSAID (2), the preparation thereof and the use thereof for the treatment of respiratory complaints.
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- NOVEL [3,2-c] HETEROARYL STEROIDS AS GLUCOCORTICOID RECEPTOR AGONISTS, COMPOSITIONS AND USES THEREOF
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The present invention provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, or isomers of said compounds), having the general structure: Formula (I) wherein L, R1, R2, R
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Page/Page column 188-189
(2010/12/31)
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- Synthesis and characterization of oxazolopyridine and benzoxazole derivatives
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Synthesis of piperazinyl-substituted oxazolopyridine and benzoxazole was achieved in three steps starting from aminophenol and carbon disulfide. Condensation of aminophenols with carbon disulfide in ethanol using potassium hydroxide as catalyst gave the required benzoxazole thiol in one step. Treatment of the thiol with piperazine and substituted piperazine derivatives in toluene furnished the titled compounds in good yield. We introduced halogen substitution in the pendant arm of the piperazine derivatives for versatile functionalization. We report the synthesis and characterization of these compounds using high resolution NMR techniques.
- Venkatachalam,Pierens,Reutens
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p. 519 - 527
(2015/03/03)
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- A new series of amodiaquine analogues modified in the basic side chain with in vitro antileishmanial and antiplasmodial activity
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The synthesis and the study of new amodiaquine derivatives bearing modified lateral basic chains as new agents with both antimalarial and antileishmanial activities are reported. The compounds were tested in vitro against Leishmania donovani MHOM/ET/67/HU3 and 2 strains of Plasmodium falciparum, 3D7 and K1. All the compounds show complex ionisation profiles. At physiological pH the ionised form(s) are in equilibrium with the uncharged form, while at acid pH all the products exist largely as protonated forms. The antiprotozoal profile indicates that all derivatives are endowed with both antimalarial and antileishmanial activity. Interestingly amodiaquine, together with some synthesised derivatives (11, 12, 15, 27, 34), displayed antileishmanial activity in the low micromolar range, although these compounds were also cytotoxic and have a narrow therapeutic window, most of the synthesised compounds proved to be potent antimalarials, a few of them showing a good activity against the chloroquine resistant K1 strain.
- Guglielmo, Stefano,Bertinaria, Massimo,Rolando, Barbara,Crosetti, Marco,Fruttero, Roberta,Yardley, Vanessa,Croft, Simon L.,Gasco, Alberto
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scheme or table
p. 5071 - 5079
(2010/01/16)
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- TRIAZOLE DERIVATIVES HAVING ANTIFUNGAL ACTIVITY, METHOD FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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A triazole derivative of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof is superior to the conventional antifungal drugs in antifungal activity against a wide spectrum of pathogenic fungi, and has advantageously low toxicity.
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Page/Page column 24
(2009/01/24)
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- Aryl sulfonamide and sulfonyl compounds as modulators of PPAR and methods of treating metabolic disorders
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Aryl sulfonamide and sulfonyl compounds as modulators of peroxisome proliferator activated receptors, pharmaceutical compositions comprising the same, and methods of treating disease using the same are disclosed.
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Page/Page column 50
(2010/02/14)
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- Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl or pyrrolyl, or cycloalkenyl R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; and Z is optionally substituted aryl or heteroaryl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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(2008/06/13)
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- 2-Alkynyl-and 2-alkenyl-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; R6 is H, alkyl, hydroxyalkyl or —CH2F; R7, R8 and R9 are H, alkyl, alkoxy, alkylthio, alkoxyalkyl, halo or —CF3; and Z is optionally substituted aryl, heteroaryl or heteroaryl-alkyl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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- Serotonin 5-HT3 receptor partial activator
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This invention provides a serotonin 5-HT3 receptor partial activator which has a serotonin 5-HT3 receptor activating action, in addition to its serotonin 5-HT3 receptor antagonism, and does not cause constipation as a side effect. Particularly, based on the finding that newly synthesized benzoxazole derivatives typified by the compounds of the following formula (2) have strong serotonin 5-HT3 receptor antagonism and serotonin 5-HT3 receptor activating action, this invention provides these benzoxazole derivatives as serotonin 5-HT3 receptor partial activators. In the above formula, R1 to R4 may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R1 and R2 may be linked together to form a ring structure, namely benzene ring; R5 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; and m is an integer of 1 to 4.
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- A new 5-HT3 receptor ligand. II. Structure-activity analysis of 5-HT3 receptor agonist action in the gut
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Several modified 2-piperazinyl benzoxazole derivatives, which exhibit an agonistic effect on gastrointestinal motility, were synthesized and their effects on the contraction of guinea-pig ileum were examined. The quaternary piperazinyl benzoxazole structure has a restricted conformation and stereostructure compared to those of the other 5-HT3 receptor agonists, serotonin and meta-chlorophenylbiguanide. The mutual positions of the aromatic ring, nitrogen atom and terminal amine are considered to form the pharmacophore of the 5-HT3 receptor agonist in the gut. In the serotonin- evoked reflex bradycardia [Bezold-Jarisch (B-J) reflex] inhibition test using rats the B-J reflex-inducing ratio was different for each synthesized compound. These results suggest that, in these 5-HT3 receptor agonists, the substituents of the benzoxazole ring influence the B-J reflex-inducing activity in rats.
- Yamada, Megumi,Sato, Yasuo,Kobayashi, Kazuko,Konno, Fukio,Soneda, Tomoko,Watanabe, Takashi
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p. 445 - 451
(2007/10/03)
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- Benzoxazole derivatives as novel 5-HT3 receptor partial agonists in the gut
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A series of benzoxazoles with a nitrogen-containing heterocyclic substituent at the 2-position was prepared and evaluated for 5-HT3 partial agonist activity on isolated guinea pig ileum. The nature of the substituent at the 5-position of the benzoxazole ring affected the potency for the 5-HTs receptor, and the 5-chloro derivatives showed increased potency and lowered intrinsic activity. 5-Chloro-7-methyl-2-(4-methyl-1- homopiperazinyl)benzoxazole (6v) exhibited a high binding affinity in the same range as that of the 5-HT3 antagonist granisetron, and its intrinsic activity was 12% of that of 5-HT. Compound 6v inhibited 5-HT-evoked diarrhea but did not prolong the transition time of glass beads in the normal distal colon even at a dose of 100 times the ED50 for diarrhea inhibition in mice. Compounds of this type are expected to be effective for the treatment of irritable bowel syndrome without the side effect of constipation.
- Sato, Yasuo,Yamada, Megumi,Yoshida, Satoshi,Soneda, Tomoko,Ishikawa, Midori,Nizato, Tetsutaro,Suzuki, Kokichi,Konno, Fukio
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p. 3015 - 3021
(2007/10/03)
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- REMEDIES OR PREVENTIVES FOR AIDS
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The present invention is to provide the combined use of one kind or two or more kinds of a quinolone carboxylic acid having anti-HIV activity and one kind or two or more kinds of a reverse transcriptase inhibitor or HIV protease inhibitor, and an AIDS therapeutic agent or preventive agent containing as its active ingredients one kind or two or more kinds of a quinolone carboxylic acid having anti-HIV activity and one kind or two or more kinds of a reverse transcriptase inhibitor or HIV protease inhibitor.
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- BENZOXAZOLE DERIVATIVES
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A benzoxazole derivative of the formula (1) or (2) which has an alicyclic diamine group at the 2-position: STR1 wherein R 1, R. sup.2, R 3, R 4, R 5, R 6, X -, m and n are defined herein. The compound shows excellent 5-HT 3 receptor antagonism and is useful as an antiemetic agent, a peristalsis controlling agent, an analgesic agent, an antianxiety agent and a schizophrenia treating agent.
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- Aryl group- or aromatic heterocyclic group-substituted aminoquinolone derivatives and anti-HIV agent
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Disclosed are an aryl group- or heterocyclic group-substituted aminoquinolone compound represented by the formula (Ia), (Ib) or (Ic): STR1 wherein each of the substitutents are defined in the specification, or a salt of the compound, and an AIDS curing agent containing the same as an effective ingredient.
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- 2-aryl-3-(substituted piperazinyl)-1-(1H-1,2,4-triazolyl)propanol-2-ol antifungal agents
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An antifungal agent of the formula: STR1 wherein R is phenyl group which may be substituted by 1 to 3 substituents each independently selected from halo and CF3 ; R1 is either (a) a phenyl group substituted by a group of the formula
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