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Oliver C Kappe - One of the best experts on this subject based on the ideXlab platform.
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microwave assisted three component synthesis of 7 aryl 2 alkylthio 4 7 dihydro 1 2 4 triazolo 1 5 a pyrimidine 6 Carboxamides and their selective reduction
ACS Combinatorial Science, 2006Co-Authors: Valentin A Chebanov, Oleg V. Shishkin, Elena A Muravyova, S M Desenko, Vladimir I Musatov, Irina V Knyazeva, Svetlana V Shishkina, Oliver C KappeAbstract:Multicomponent reactions (MCRs) and microwave-assisted organic synthesis (MAOS) have been used as key methods for the synthesis of fused dihydropyrimidine derivatives. The three-component condensation of 3-amino-5-alkylthio-1,2,4-triazoles with aromatic aldehydes and acetoacetamides under microwave irradiation was developed as a rapid and efficient solution-phase method for the high-yielding preparation of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-Carboxamide libraries. In addition, the selective reduction of the formed dihydrotriazolopyrimidines to trans-trans-2-alkylthio-7-aryl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine-6-Carboxamides was established. The described synthetic protocols provide rapid access to novel and diversely substituted dihydroazolopyrimidine libraries.
Pradip K Mascharak - One of the best experts on this subject based on the ideXlab platform.
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dye tethered ruthenium nitrosyls containing planar diCarboxamide tetradentate n4 ligands effects of in plane ligand twist on no photolability
Inorganic Chemistry, 2011Co-Authors: Nicole L Fry, Brandon J Heilman, Pradip K MascharakAbstract:To examine the steric effects of the in-plane ligands in dye-sensitized {RuNO}(6) nitrosyls on their NO photolability, two new ligands, namely, 1,2-Bis(pyridine-2-carboxamido)-4,5-dimethoxybenzene (H(2)(OMe)(2)bpb) and 1,2-Bis(Isoquinoline-1-carboxamido)-4,5-dimethoxybenzene (H(2)(OMe)(2)IQ1, H's are dissociable Carboxamide protons) have been designed and synthesized. The syntheses and spectroscopic properties of {RuNO}(6) nitrosyls derived from these two ligands, namely, [((OMe)(2)bpb)Ru(NO)(Cl)] (4-Cl), [((OMe)(2)IQ1)Ru(NO)(Cl)] (5-Cl), [((OMe)(2)bpb)Ru(NO)(Resf)] (4-Resf), and [((OMe)(2)IQ1)Ru(NO)(Resf)] (5-Resf), are reported. The structures of 5-Cl, 4-Resf, and 5-Resf have been determined by X-ray crystallography. Removal of the in-plane ligand twist in the quinoline-based R(2)bQb(2-) ligand frame (because of steric interactions between the extended quinoline ring systems) in both R(2)bpb(2-) and R(2)IQ1(2-) (pyridine and 1-isoquinoline rings, respectively, instead of quinoline rings in the equatorial plane) results in enhanced solution stability, as well as higher quantum yield values for NO photorelease upon exposure to 500 nm light. Both dye-tethered {RuNO}(6) nitrosyls 4-Resf and 5-Resf exhibit greater sensitivity to visible light compared to the chloro-bound species 4-Cl and 5-Cl. In addition, the dye-tethered nitrosyls are fluorescent and hence can be used as trackable NO donors in cellular studies.
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ruthenium nitrosyls derived from polypyridine ligands with Carboxamide or imine nitrogen donor s isoelectronic complexes with different no photolability
Inorganic Chemistry, 2007Co-Authors: Michael J Rose, Apurba K Patra, Eric A Alcid, M M Olmstead, Pradip K MascharakAbstract:As part of our search for photoactive ruthenium nitrosyls, a set of {RuNO}6 nitrosyls has been synthesized and structurally characterized. In this set, the first nitrosyl [(SBPy3)Ru(NO)](BF4)3 (1) is derived from a polypyridine Schiff base ligand SBPy3, while the remaining three nitrosyls are derived from analogous polypyridine ligands containing either one ([(PaPy3)Ru(NO)](BF4)2 (2)) or two ([(Py3P)Ru(NO)]BF4 (3) and [(Py3P)Ru(NO)(Cl)] (4)) Carboxamide group(s). The coordination structures of 1 and 2 are very similar except that in 2, a carboxamido nitrogen is coordinated to the ruthenium center in place of an imine nitrogen in case of 1. In 3 and 4, the ruthenium center is coordinated to two carboxamido nitrogens in the equatorial plane and the bound NO is trans to a pyridine nitrogen (in 3) and chloride (in 4), respectively. Complexes 1−3 contain N6 donor set, and the NO stretching frequencies (νNO) correlate well with the N−O bond distances. All four diamagnetic {RuNO}6 nitrosyls are photoactive and r...
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a synthetic analogue of the active site of fe containing nitrile hydratase with carboxamido n and thiolato s as donors synthesis structure and reactivities
Journal of the American Chemical Society, 2001Co-Authors: Juan C Noveron, Marilyn M Olmstead, Pradip K MascharakAbstract:As part of our work on models of the iron(III) site of Fe-containing nitrile hydratase, a designed ligand PyPSH4 with two Carboxamide and two thiolate donor groups has been synthesized. Reaction of (Et4N)[FeCl4] with the deprotonated form of the ligand in DMF affords the mononuclear iron(III) complex (Et4N)[FeIII(PyPS)] (1) in high yield. The iron(III) center is in a trigonal bipyramidal geometry with two deprotonated carboxamido nitrogens, one pyridine nitrogen, and two thiolato sulfurs as donors. Complex 1 is stable in water and binds a variety of Lewis bases at the sixth site at low temperature to afford green solutions with a band around 700 nm. The iron(III) centers in these six-coordinate species are low-spin and exhibit EPR spectra much like the enzyme. The pKa of the water molecule in [FeIII(PyPS)(H2O)]- is 6.3 ± 0.4. The iron(III) site in 1 with ligated carboxamido nitrogens and thiolato sulfurs does not show any affinity toward nitriles. It thus appears that at physiological pH, a metal-bound hy...
Naoyuki Yoshida - One of the best experts on this subject based on the ideXlab platform.
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synthesis and structure affinity relationships of novel n 1 ethyl 4 methylhexahydro 1 4 diazepin 6 yl pyridine 3 Carboxamides with potent serotonin 5 ht3 and dopamine d2 receptor antagonistic activity
Journal of Medicinal Chemistry, 2003Co-Authors: Yoshimi Hirokawa, Iwao Fujiwara, Kenji Suzuki, Hiroshi Harada, Takashi Yoshikawa, Naoyuki YoshidaAbstract:A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-Carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D2 and serotonin 5-HT3 receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-Carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT3 receptor along with moderate to high binding affinity for the dopamine D2 receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D2 receptor while keeping a potent serotonin 5-HT3 receptor binding affinity. As a result of structure−affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-Carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D2 and serotonin 5-HT...
Shannon S Stahl - One of the best experts on this subject based on the ideXlab platform.
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discovery and mechanistic study of aliii catalyzed transamidation of tertiary amides
Journal of the American Chemical Society, 2008Co-Authors: Justin M Hoerter, Karin M Otte, Samuel H. Gellman, Shannon S StahlAbstract:Cleavage of the C−N bond of Carboxamides generally requires harsh conditions. This study reveals that tris(amido)AlIII catalysts, such as Al2(NMe2)6, promote facile equilibrium-controlled transamidation of tertiary Carboxamides with secondary amines. The mechanism of these reactions was investigated by kinetic, spectroscopic, and density functional theory (DFT) computational methods. The catalyst resting state consists of an equilibrium mixture of a tris(amido)AlIII dimer and a monomeric tris(amido)AlIII−Carboxamide adduct, and the turnover-limiting step involves intramolecular nucleophilic attack of an amido ligand on the coordinated Carboxamide or subsequent rearrangement (intramolecular ligand substitution) of the tetrahedral intermediate. Fundamental mechanistic differences between these tertiary transamidation reactions and previously characterized transamidations involving secondary amides and primary amines suggest that tertiary amide/secondary amine systems are particularly promising for future de...
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mechanism of aliii catalyzed transamidation of unactivated secondary Carboxamides
Journal of the American Chemical Society, 2006Co-Authors: Justin M Hoerter, Karin M Otte, Samuel H. Gellman, Shannon S StahlAbstract:The carbon−nitrogen bond of secondary Carboxamides is generally thermodynamically and kinetically unreactive; however, we recently discovered that the trisamidoaluminum(III) dimer Al2(NMe2)6 catalyzes facile transamidation between simple secondary Carboxamides and primary amines under moderate conditions. The present report describes kinetic and spectroscopic studies that illuminate the mechanism of this unusual transformation. The catalytic reaction exhibits a bimolecular rate law with a first-order dependence on the AlIII and amine concentrations. No rate dependence on the Carboxamide concentration is observed. Spectroscopic studies (1H and 13C NMR, FTIR) support a catalyst resting state that consists of a mixture of tris-(κ2-amidate)aluminum(III) complexes. These results, together with the presence of a significant kinetic isotope effect when deuterated amine substrate (RND2) is used, implicate a mechanism in which the amine undergoes preequilibrium coordination to aluminum and proton transfer to a κ2-...
Natalia Realini - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and biological evaluation of a series of oxazolone Carboxamides as a novel class of acid ceramidase inhibitors
Journal of Medicinal Chemistry, 2020Co-Authors: Samantha Caputo, Ilaria Penna, Debora Russo, Simona Di Martino, Vincenzo Cilibrasi, Piero Tardia, Marco Mazzonna, Maria Summa, Sine Mandrup Bertozzi, Natalia RealiniAbstract:Acid ceramidase (AC) is a cysteine hydrolase that plays a crucial role in the metabolism of lysosomal ceramides, important members of the sphingolipid family, a diversified class of bioactive molecules that mediate many biological processes ranging from cell structural integrity, signaling, and cell proliferation to cell death. In the effort to expand the structural diversity of the existing collection of AC inhibitors, a novel class of substituted oxazol-2-one-3-Carboxamides were designed and synthesized. Herein, we present the chemical optimization of our initial hits, 2-oxo-4-phenyl-N-(4-phenylbutyl)oxazole-3-Carboxamide 8a and 2-oxo-5-phenyl-N-(4-phenylbutyl)oxazole-3-Carboxamide 12a, which resulted in the identification of 5-[4-fluoro-2-(1-methyl-4-piperidyl)phenyl]-2-oxo-N-pentyl-oxazole-3-Carboxamide 32b as a potent AC inhibitor with optimal physicochemical and metabolic properties, showing target engagement in human neuroblastoma SH-SY5Y cells and a desirable pharmacokinetic profile in mice, following intravenous and oral administration. 32b enriches the arsenal of promising lead compounds that may therefore act as useful pharmacological tools for investigating the potential therapeutic effects of AC inhibition in relevant sphingolipid-mediated disorders.
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Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies
Journal of Medicinal Chemistry, 2015Co-Authors: Anders Bach, Valentina Vozella, Daniela Pizzirani, Natalia Realini, Laurin Melzig, Ilaria Penna, Debora Russo, Rita ScarpelliAbstract:Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone Carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and Carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity?stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.
