- Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice
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Stress in our daily life severely affects the normal physiology of the biological system. Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of depression-like behavior, which remains under diagnosed and poorly treated. Exogenous corticosterone (CORT) administration has been demonstrated to develop a depression model, which has shown to mimic HPA-axis induced depression-like state in rodents. In the present study, the effect of a novel 5HT3 receptor, 4i was examined on CORT induced depression in mice. CORT (30 mg/kg, subcutaneously) was given for 4-weeks to mice in control group, while mice in drug treated group were given 4i (0.5-1 mg/kg, intraperitoneally)/fluoxetine (as a positive control, 10 mg/kg), for the last 2-weeks of CORT dosing. Repeated CORT dosing caused depression-like behavior in mice as indicated by increased despair effects in forced swim test (FST) and anhedonia in sucrose preference test. In addition, CORT administration induced oxidative load in the brain with significant increase in pro-oxidant (lipid peroxidation and nitrite levels) markers and a substantial decline in anti-oxidant defense (catalase and reduced glutathione levels) system, indicating a direct effect of stress hormones in the induction of the brain oxidative damage. On the other hand, 4i and fluoxetine treatment reversed the CORT induced depressive-like deficits. Furthermore, 4i and fluoxetine prevented CORT induced oxidative brain insults, which may plausibly demonstrate one of the key mechanisms for antidepressant-like effects of the compounds. Thus, the study suggests that 5HT3 antagonist; 4i may be implicated as pharmacological intervention targeting depressive-like anomaly associated with HPA-axis dysregulation.
- Gupta, Deepali,Radhakrishnan, Mahesh,Kurhe, Yeshwant
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Read Online
- Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors
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Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.
- Platte, Simon,Korff, Marvin,Imberg, Lukas,Balicioglu, Ilker,Erbacher, Catharina,Will, Jonas M.,Daniliuc, Constantin G.,Karst, Uwe,Kalinin, Dmitrii V.
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supporting information
p. 3672 - 3690
(2021/08/07)
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- Antidepressant and anti-anxiety like effects of 4i (N-(3-chloro-2- methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist in acute and chronic neurobehavioral rodent models
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Depression and anxiety are the most debilitating mood disorders with poor therapeutic recovery rates. In the last decades, 5-HT3 receptor antagonists have been identified as potential agents for mood disorders. The current investigation focuses on evaluating the, antidepressant and anti-anxiety like effects of a novel 5-HT3 antagonist, 4i (N-(3-chloro-2- methylphenyl) quinoxalin-2-carboxamide). Preliminary, in vitro 5-HT3 receptor binding affinity was performed in isolated longitudinal muscle-myenteric plexus from the guinea pig ileum. Consequently, neurobehavioral effects of 4i in acute and chronic rodent models were evaluated. In addition, involvement of serotonergic system in the postulated effects of the compound was analyzed by in vivo assay. in vitro, 4i demonstrated high 5-HT3 receptor antagonistic activity (pA2, 7.6). in vivo acute study, 4i exhibited decreased duration of immobility in forced swim and tail suspension tests, and increased exploratory parameters as number and duration of nose-poking in hole board test and latency and time spent in aversive brightly illuminated light chamber in light-dark model. Moreover, in chronic model of depression, i.e., olfactory bulbectomy with behavioral deficits, 4i reversed depressive anhedonia in sucrose preference test and anxious hyperactive behavior in open field test in rats. Furthermore, synergistic effect of 4i with fluoxetine (a selective serotonin reuptake inhibitor) and inhibitory effect of 1-(m-chlorophenyl)- biguanide (a 5-HT3 receptor agonist) revealed serotonergic modulation by 4i mediated 5-HT3 receptor antagonism, which was further confirmed by potentiation of 5-hydroxytryptophan (a serotonin synthesis precursor) induced head twitch response. These findings suggest the potential antidepressant and anti-anxiety like effects of 4i, which may be related to the modulation of serotonergic system.
- Gupta, Deepali,Radhakrishnan, Mahesh,Thangaraj, Devadoss,Kurhe, Yeshwant
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supporting information
p. 59 - 67
(2014/05/20)
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- Cationic porphyrin-quinoxaline conjugate as a photochemically triggered novel cytotoxic agent
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A novel cationic porphyrin-quinoxaline conjugate 8 was prepared in good yield by the coupling of activated quinoxaline carboxylic acid 5 with an appropriate aminoporphyrin. The UV-vis spectra of conjugate 8 with the addition of ctDNA shows substantial hyp
- Kumar, Dalip,Chandra Shekar,Mishra, Bhupendra,Kurihara, Ryohsuke,Ogura, Maiko,Ito, Takeo
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p. 3221 - 3224
(2013/06/27)
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- PROTEIN KINASE INHIBITORS AND METHODS OF TREATMENT
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The present invention relates to chemical compounds of formula (I) and methods for their use and preparation. In particular, the invention relates to substituted pyrazolo[3,4-d]pyrimidine based compounds which can be used in treating proliferative disorders, use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds.
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Page/Page column 68
(2012/02/01)
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- Quinoxalin-2-carboxamides: Synthesis and pharmacological evaluation as serotonin type-3 (5-HT3) receptor antagonists
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A series of quinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT3 receptor antagonists and synthesized by condensing the carboxylic group of quinoxalin-2-carboxylic acid with various amines in the presence of 1
- Mahesh, Radhakrishnan,Devadoss, Thangaraj,Pandey, Dilip Kumar,Yadav, Shushil Kumar
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experimental part
p. 610 - 615
(2012/04/23)
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- Design, synthesis and structure-activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression
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A novel series of quinoxalin-2-carboxamides were designed based on the ligand-based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by spectral data. The target new chemical entities were evaluated for their 5-HT3 receptor antagonisms in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT3 agonist, 2-methyl-5-HT, which was expressed in the form of pA2 value. All the synthesized compounds showed antagonism towards 5-HT3 receptor; based on this result, a structure-activity relationship was derived, which reveals that the aromatic residue in 5-HT3 receptor antagonists may have hydrophobic interaction with 5-HT3 receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA2 values exhibited good anti-depressant-like activity as compared to the vehicle-treated group.
- Mahesh, Radhakrishnan,Devadoss, Thangaraj,Pandey, Dilip Kumar,Bhatt, Shvetank,Yadav, Shushil Kumar
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scheme or table
p. 6773 - 6776
(2010/12/20)
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- An efficient synthesis of 2-quinoxalinecarboxylic acid
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Development of a cost efficient and scaleable process for 2-quinoxalinecarboxylic acid is described. The primarily goals of the development work were to improve the overall yield of the process, to minimize the use of environmentally unacceptable material
- Harms, Arthur E.
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p. 666 - 669
(2013/09/02)
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- Biocatalytic oxidation of 2-methylquinoxaline to 2-quinoxalinecarboxylic acid
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A microbial process using the fungus Absidia repens ATCC 14849 is described for the oxidation of 2-methylquinoxaline to 2-quinoxalinecarboxylic acid. A campaign consisting of three 14000-L runs produced 20.5 kg of the acid with a 28% overall yield. The bioconversion gave a lower yield compared with a three step chemical synthesis (35%), but was carried out in one pot, and avoided safety issues with a di-N-oxide intermediate. Although successfully scaled to produce kilograms of 2-quinoxalinecarboxylic acid for synthesis of a drug candidate, the A. repens bioconversion is unsuitable for further scale-up due to low product concentration (~1 g/L). A second microbial process using Pseudomonas putida ATCC 33015 is also described for the oxidation of 2-methylquinoxaline. The P. putida bioconversion gave an 86% in situ yield at 8-L scale and yielded a product concentration approximately 10-fold greater than that of the A. repens bioconversion.
- Wong, John W.,Watson Jr., Harry A.,Bouressa, James F.,Burns, Michael P.,Cawley, James J.,Doro, Albert E.,Guzek, Donald B.,Hintz, Michael A.,McCormick, Ellen L.,Scully, Douglas A.,Siderewicz, Joseph M.,Taylor, William J.,Truesdell, Susan J.,Wax, Richard G.
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p. 477 - 481
(2013/09/06)
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- Novel reversible indole-3-carboxylate decarboxylase catalyzing nonoxidative decarboxylation
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After enrichment culture with indole-3-carboxylate in static culture, a novel reversible decarboxylase, indole-3-carboxylate decarboxylase, was found in Arthrobacter nicotianae FI1612 and several molds. The enzyme reaction was examined in resting-cell reactions with A. nicotianae FI1612. The enzyme activity was induced specifically by indole-3-carboxylate, but not by indole. The indole-3-carboxylate decarboxylase of A. nicotianae FI1612 catalyzed the nonoxidative decarboxylation of indole-3-carboxylate into indole, and efficiently carboxylated indole and 2-methylindole by the reverse reaction. In the presence of 1 mM dithiothreitol, 50 mM Na2 S2O 3, and 20% (v/v) glycerol, indole-3-carboxylate decarboxylase was partially purified from A. nicotianae FI1612. The purified enzyme had a molecular mass of approximately 258 kDa. The enzyme did not need any cofactor for the decarboxylating and carboxylating reactions.
- Yoshida, Toyokazu,Fujita, Kohei,Nagasawa, Toru
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p. 2388 - 2394
(2007/10/03)
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- Inhibitors of HIV protease
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Compounds of formula (I): STR1 wherein: R1 is hydrogen, alkyl, aralkyl, --CORa, --CORb, --CSRa, --CSRb, --SO2 Rb, --CONHRb, --CSNHRb, --CONRb Rb or --CSNRb Rb ; R2 is hydrogen or alkyl; R3 is hydrogen, alkylidene, substituted alkyl, or Rb ; R4 is optionally substituted alkyl, cycloalkyl, or aryl; R5 is Rb O--, Rb Rb N--, Rb HN--, aralkyloxycarbonyloxy or aralkyloxycarbonylamino, or R5 is --(CH2)p --D--(CH2)r --, where D is a single bond, carbonyl, oxygen, sulfur, --NH--, --(CH2 =CH2)-- or --NHCO--; and p and r are each 0 or an integer from 1 to 5; A is --(CH2)m --B--(CH2)n -- where B is a single bond, carbonyl, oxygen, sulfur, --NH--, --(CH2 =CH2)-- or --NHCO--; and m and n are each 0 or an integer from 1 to 5; Ra is alkoxy, aralkyloxy, aryloxy or alkoxycarbonyl; Rb is optionally substituted alkyl, cycloalkyl, heterocyclic, aryl or arylalkenyl; and pharmaceutically acceptable salts and esters thereof and pro-drugs therefor, have the ability to inhibit the activity of HIV protease and may thus be used for the treatment and prophylaxis of AIDS.
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- Oxidation of 2,3-Dimethyl-quinoxaline and 2,4-Dimethyl-quinazoline with Selenium Dioxide
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The primary oxidation products of 2,3-dimethylquinoxaline with selenium dioxide are 3-methylquinoxaline-2-carbaldehyde, 1,3-dihydro-1,3-dihydroxyfuroquinoxaline and quinoxaline-2-carboxylic acid. 3-Methylquinoxaline-2-carboxylic acid can be obtained in a second oxidation step only. 2,4-Dimethylquinazoline is dehydrogenated by selenium dioxide to the heterocyclic stilbene derivative 8.Confirmation of structure of 8 is given by NMR spectroscopy. - Keywords: Oxidation of methyl groups; SeO2; Quinoxaline; Quinazoline
- Kepez, Mustafa
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p. 127 - 130
(2007/10/02)
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