- Stereoelectronic and Resonance Effects on the Rate of Ring Opening of N-Cyclopropyl-Based Single Electron Transfer Probes
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N-Cyclopropyl-N-methylaniline (5) is a poor probe for single electron transfer (SET) because the corresponding radical cation undergoes cyclopropane ring opening with a rate constant of only 4.1 × 104 s-1, too slow to compete with other processes such as radical cation deprotonation. The sluggish rate of ring opening can be attributed to either (i) a resonance effect in which the spin and charge of the radical cation in the ring-closed form is delocalized into the phenyl ring, and/or (ii) the lowest energy conformation of the SET product (5a¢+) does not meet the stereoelectronic requirements for cyclopropane ring opening. To resolve this issue, a new series of N-cyclopropylanilines were designed to lock the cyclopropyl group into the required bisected conformation for ring opening. The results reveal that the rate constant for ring opening of radical cations derived from 1′-methyl-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-quinoline] (6) and 6′-chloro-1′-methyl-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-quinoline] (7) are 3.5 × 102 s-1 and 4.1 × 102 s-1, effectively ruling out the stereoelectronic argument. In contrast, the radical cation derived from 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline (8) undergoes cyclopropane ring opening with a rate constant of 1.7 × 108 s-1, demonstrating that loss of the resonance energy associated with the ring-closed form of these N-cyclopropylanilines can be amply compensated by incorporation of a radical-stabilizing phenyl substituent on the cyclopropyl group. Product studies were performed, including a unique application of EC-ESI/MS (Electrochemistry/ElectroSpray Ionization Mass Spectrometry) in the presence of 18O2 and H218O to elucidate the mechanism of ring opening of 7a¢+ and trapping of the resulting distonic radical cation.
- Grimm, Michelle L.,Suleman, N. Kamrudin,Hancock, Amber N.,Spencer, Jared N.,Dudding, Travis,Rowshanpour, Rozhin,Castagnoli, Neal,Tanko, James M.
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- Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model
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Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and sel
- Shen, Sida,Picci, Cristina,Ustinova, Kseniya,Benoy, Veronick,Kutil, Zsófia,Zhang, Guiping,Tavares, Maurício T.,Pavlí?ek, Ji?í,Zimprich, Chad A.,Robers, Matthew B.,Van Den Bosch, Ludo,Ba?inka, Cyril,Langley, Brett,Kozikowski, Alan P.
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p. 4810 - 4840
(2021/05/07)
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- Synthesis, in silico Study and Antileishmanial Evaluation of New Selenides Derived from 7-Chloro-quinoline and N-Phenylacetamides
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This study describes a virtual screening performed for two series of selenides (28 compounds), derived from N-phenylacetamides chlorides and 7-chloro-quinoline, to determine their potential for leishmanicidal activity against Leishmania amazonensis and Leishmania donovani. Seven compounds were predicted as potential leishmanicides; therefore, they were synthesized from elemental selenium, as a precursor for the production of NaHSe, and subsequent reactions with 4,7-dichloro-quinoline and N-phenylacetamides chlorides were performed. The compounds were characterized by infrared (IR), 1H and 13C nuclear magnetic resonance (NMR), and sent for in vitro cytotoxicity tests against L. amazonensis and were found to be active and selective, and two compounds presented half-maximal inhibitory concentrations (IC50) of 5.67 and 10.81 μg mL-1. They also presented good interaction energies in the docking study, suggesting that may exert their effects by inhibiting the N-myristoyltransferase and O-acetylserine sulfhydrylase enzymes in parasites.
- Huang, Min-Fu N.,Luis, José A.S.,da Silva, Alison P.,Rocha, Juliana C.,Lima, Tatjana K.S.,Scotti, Marcus T.,Scotti, Luciana,de Oliveira, Rafael F.,Souza, Helivaldo D.S.,de Athayde-Filho, Petr?nio F.,Barbosa-Filho, José M.
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p. 712 - 721
(2021/03/17)
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- Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome
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Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological a
- Kozikowski, Alan P.,Shen, Sida,Pardo, Marta,Tavares, Maurício T.,Szarics, Dora,Benoy, Veronick,Zimprich, Chad A.,Kutil, Zsófia,Zhang, Guiping,Ba?inka, Cyril,Robers, Matthew B.,Van Den Bosch, Ludo,Eubanks, James H.,Jope, Richard S.
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p. 1679 - 1695
(2019/01/04)
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- Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models
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Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.
- Shen, Sida,Hadley, Melissa,Ustinova, Kseniya,Pavlicek, Jiri,Knox, Tessa,Noonepalle, Satish,Tavares, Mauricio T.,Zimprich, Chad A.,Zhang, Guiping,Robers, Matthew B.,Ba?inka, Cyril,Kozikowski, Alan P.,Villagra, Alejandro
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p. 8557 - 8577
(2019/10/02)
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- Synthesis of some 1,2,4-triazoles as potential anti-tubercular agents
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A series of 5-(N-substituted carboxamidoethylthio)-3-(3'pyridyl)-4- amino-1,2,4-triazole derivatives 6a-j have been synthesized and evaluated for anti-tubercular activity. They are screened in-vitro at 10μg/mL concentration against Mycobacterium tuberculosis H37RV (ATCC 27294). All the compounds are showing antitubercular activity when compared with the standard drug Amikacin. Compounds 6e and 6h are found active as they displayed IC50 and IC90 values at 100μg/mL.
- Vijayaraghavan,Shirodkar
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p. 1149 - 1153
(2015/09/28)
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- In silico and experimental identification of non ulcerogenic antiinflammatory agents: 3-Thio substituted-4,5-diaryl-4H-1,2,4-triazoles
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A new series of 4,5 diaryl-1,2,4-triazole-3-thione substituted carboxamides have been designed, synthesized and tested for their analgesic and antiinflammatory potential. All the tested compounds exhibit antiinflammatory activity comparable to that of standard drugs rofecoxib and diclofenac. Some compounds demonstrate significant analgesic activity in contrast to reference drugs. Compound 9c has emerged as a highly potent lead compound. Ulcerogenic studies of synthesized compounds and rofecoxib show nil or negligible ulcerogenic effect compared to diclofenac. In silico analysis (docking studies) of the most active compound 9c has revealed hypothetical binding mode of the target compound to the cyclooxygenase isoenzyme (COX-2). Docking study has anticipated stereoselective binding mode for the most active compound 9c.
- Khatale, Pravin N.,Sivakumar,Mahajan, Niranjan S.,Jawarkar, Rahul D.,Kedar, Chakor K.
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p. 890 - 899
(2014/08/05)
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- Design and synthesis of new 8-anilide theophylline derivatives as bronchodilators and antibacterial agents
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Theophylline derivatives have long been recognized as potent bronchodilators for the relief of acute asthma. Recently, it was found that bacterial infection has a role in asthma pathogenesis. The present work involves the design and synthesis of 8-substituted theophylline derivatives as bronchodilators and antibacterial agents. The chemical structures of these compounds were elucidated by IR, 1H-NMR, mass spectrometry, and elemental analyses. The bronchodilator activity was evaluated using acetylcholine-induced bronchospasm in guinea pigs, and most of the compounds showed significant anti-bronchoconstrictive activity in comparison with standard aminophylline. In addition, the antibacterial activity of all the target compounds was investigated in vitro against Gram-positive and Gram-negative bacteria using ampicillin as a reference drug. Results showed that some of the tested compounds possessed significant antibacterial activity. A pharmacophore model was computed to obtain useful insight into the essential structural features of bronchodilator activity. A structure activity relationship was also discussed.
- Hayallah, Alaa M.,Talhouni, Ahmad A.,Abdel Alim, Abdel Alim M.
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p. 1355 - 1368
(2013/01/15)
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- Synthesis and biological screening of novel derivatives of 3-(N-substituted carboxamidoethylthio)-(4H)-1,2,4-triazoles
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3-Mercapto-(4H)-1,2,4-triazole has been synthesized from 1-formylthiosemicarbazide. Different N-substituted β-chloropropionamides have been prepared by reacting substituted amines with β- chloropropionylchloride. Different Nsubstituted β-chloropropionamides have been condensed with 3-mercapto-(4H)-1,2,4-triazole in basic medium to obtain various 3-(N-substituted carboxamidoethylthio)-(4H)-1,2,4-triazoles. The structure of the synthesized compounds are confirmed by IR, 1H NMR spectra and elemental analysis. All the compounds have been screened for their analgesic, anti-inflammatory and anxiolytic activity.
- Manikrao, Anil M.,Fursule, Ravindra A.,Rajesh,Kunjwani, Harish K.,Sabale, Prafulla M.
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experimental part
p. 1642 - 1647
(2011/03/17)
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- NEW HETEROCYCLIC DERIVATIVES USEFUL FOR THE TREATMENT OF CNS DISORDERS
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The present invention relates to new compounds, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
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Page/Page column 95-96
(2008/12/08)
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- Benzo[c]quinolizin-3-ones: A novel class of potent and selective nonsteroidal inhibitors of human steroid 5α-reductase 1
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The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5α-reductase (5αR) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19-29) or 1H-tetrahydrobenzo[c]quinolizin-3-ones (35-47) bearing at position
- Guarna,Machetti,Occhiato,Scarpi,Comerci, Alessandra,Danza, Giovanna,Mancina, Rosa,Serio, Mario,Hardy, Kimber
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p. 3718 - 3735
(2007/10/03)
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- New heteroaryl-spaced phosphono α-amino acids are competitive NMDA antagonists with analgesic activity
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The synthesis and the NMDA receptor binding affinities of α-amino-3-(phosphonomethyl)-2-naphthalenepropanoic acid, α-amino-3-(phosphonomethyl)-2-benzofuranpropanoic acid, a series of substituted (R)-α-amino-3-(phosphonomethyl)-2-quinolinepropanoic acids, (R)-α-amino-3-(phosphonomethyl)-1,8-naphthyridine-2-propanoic acid and (R)-α-amino-3-(phosphonomethyl)-1,6-naphthyridine-2-propanoic acid are reported.
- Swahn, Britt-Marie,Claesson, Alf,Pelcman, Benjamin,Besidski, Yevgeni,Molin, Hakan,Sandberg, Mats P.,Berge, Odd-Geir
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p. 1635 - 1640
(2007/10/03)
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