- Substituted 4-phenylthiazoles: Development of potent and selective A1, A3 and dual A1/A3 adenosine receptor antagonists
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Adenosine acts as a powerful signaling molecule via four distinct G protein-coupled receptors, designated A1, A2A, A2B and A3 adenosine receptors (ARs). A2A and A2B ARs are Gs-coupled, while A1 and A3 ARs inhibit cAMP production via Gi proteins. Antagonists for A1 and A3 ARs may be useful for the treatment of (neuro)inflammatory diseases including acute kidney injury and kidney failure, pulmonary diseases, and Alzheimer's disease. In the present study, we optimized the versatile 2-amino-4-phenylthiazole scaffold by introducing substituents at N2 and C5 to obtain A1 and A3 AR antagonists including dual-target compounds. Selective A1 antagonists with (sub)nanomolar potency were produced, e.g. 11 and 13. These compounds showed species differences being significantly more potent at the rat as compared to the human A1 AR, and were characterized as inverse agonists. Several potent and selective A3 AR antagonists, e.g. 7, 8, 17 and 22 (Ki values of 5–9 nM at the human A3 AR) were prepared, which were much less potent at the rat orthologue. Moreover, dual A1/A3 antagonists (10, 18) were developed showing Ki values between 8 and 42 nM. Docking and molecule dynamic simulation studies using the crystal structure of the A1 AR and a homology model of the A3 AR were performed to rationalize the observed structure-activity relationships.
- Abdelrahman, Aliaa,Yerande, Swapnil G.,Namasivayam, Vigneshwaran,Klapschinski, Tim A.,Alnouri, Mohamad Wessam,El-Tayeb, Ali,Müller, Christa E.
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supporting information
(2019/12/24)
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- Intramolecular alkene hydroamination and degradation of amidines: Divergent behavior of rare earth metal amidinate intermediates
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Direct N-H addition of amidines to alkenes is a highly valuable but challenging transformation that remains elusive. Now, the intramolecular hydroamidination of N-alkenylamidines is achieved by using a rare earth catalyst, which provides an efficient and atom-economical approach for substituted imidazolines and tetrahydropyrimidines. Moreover, a mild and efficient method for the catalytic degradation of amidines to give amines and nitriles is also developed. Additionally, amidine reconstruction followed by an intramolecular alkene hydroamidination strategy for the synthesis of substituted imidazolines and tetrahydropyrimidines from secondary enamines and inactive amidines has also been established, which may circumvent the need for some unavailable starting materials. The mechanistic studies prove that these reactions proceed via a key lanthanide amidinate intermediate that can undergo substrate- and amine-controlled chemodivergent transformations: intramolecular alkene insertion, nitrile extrusion, amidinate reconstruction, or a combination of the reactions. The results presented here not only demonstrate the synthetic potential and versatility of alkene hydroamidination with substrates, but also provide a good insight into the factors that promote or deter the hydroamidination of alkenes.
- Zhang, Dexing,Liu, Ruiting,Zhou, Xigeng
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p. 5573 - 5581
(2018/11/20)
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- New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides
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A series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamide and furamide analogues were investigated in radioligand binding studies at adenosine receptor subtypes with an aim to obtain potent and selective adenosine receptor ligands. Benzamide and furamide linked to thiazole was found to be crucial for high adenosine receptor affinity. The most potent compound indentified in this study was 5d with low nanomolar affinity for all four adenosine receptor subtypes. Compounds 5a and 5g showed moderate selectivity for A2A adenosine receptors. Molecular docking versus all four human adenosine receptors combined with membrane molecular dynamics studies were performed to rationalise the peculiar selectivity profile of 5d antagonist.
- Inamdar, Gajanan S.,Pandya, Amit N.,Thakar, Hardik M.,Sudarsanam, Vasudevan,Kachler, Sonja,Sabbadin, Davide,Moro, Stefano,Klotz, Karl-Norbert,Vasu, Kamala K.
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p. 924 - 934
(2013/07/27)
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- A diversified assembly of 1,2,4-oxadiazol-3-amines: Metallic thiophile catalyzed chemoselective one-pot reaction of aryl isothiocyanates, amidines/guanidines, and hydroxylamine
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An efficient one-pot synthesis of 1,2,4-oxadiazol-3-amines from simple starting materials, isothiocyanates, amidines/guanidines, and hydroxylamine, is described. The reaction is facilitated by metallic-thiophile-assisted desulfurization of in situ formed amidino- or guanidinothiourea to give chemoselectively N-hydroxyguanidine intermediates that give exclusively various 1,2,4-oxadiazol-3-amines in good to excellent yields. The reaction mechanistic pathway may proceed through an intramolecular 5-exo-trig cyclization.
- Jalani, Hitesh B.,Sudarsanam, V.,Vasu, Kamala K.
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p. 3378 - 3386,9
(2012/12/12)
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- 2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists
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A series of 2-amino-5-benzoyl-4-phenylthiazole derivatives was investigated in radioligand binding studies at adenosine receptor (AdoR) subtypes with the goal to obtain potent and A1-selective antagonists. Acylation of the 2-amino group was fou
- Scheiff, Anja B.,Yerande, Swapnil G.,El-Tayeb, Ali,Li, Wenjin,Inamdar, Gajanan S.,Vasu, Kamala K.,Sudarsanam, Vasudevan,Müller, Christa E.
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scheme or table
p. 2195 - 2203
(2010/06/12)
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- Design, synthesis and characterization of novel 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives as inhibitors of NF-κB and AP-1 mediated transcription activation and as potential anti-inflammatory agents
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A series of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives were designed and synthesized. Synthesized molecules were further evaluated for their inhibitory activity towards transcription factors NF-κB and AP-1 mediated transcr
- Giri, Rajan S.,Thaker, Hardik M.,Giordano, Tony,Williams, Jill,Rogers, Donna,Sudersanam, Vasudevan,Vasu, Kamala K.
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body text
p. 2184 - 2189
(2009/09/30)
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- Effects of structural changes on acidities and homolytic bond dissociation energies of the H-N bonds in amidines, carboxamides, and thiocarboxamides
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The equilibrium acidities in DMSO have been measured for acetamidine, benzamidine, N,N'-diphenylbenzamidine, N,N-diethylbenzamidine, diphenylmethanimine, guanidine, N,N'-diphenylguanidine, N,N'-diphenylurea, and N,N'-diphenylthiourea. Combination of the resulting pKHA values for these weak acids with the oxidation potentials of their conjugate bases gave estimates of their homolytic bond dissociation energies (BDEs). These acidities and BDEs are compared with those of the corresponding carboxamides and thiocarboxamides. The change in hybridization of nitrogen between NH3 and Ph2C=NH causes the acidities and BDEs to increase by about 14 and 9 kcal/mol, respectively. These changes are similar to the increases in gas-phase acidities and BDEs observed for the change in hybridization between CH3CH3 and CH2=CH2 (12 and 12 kcal/mol, respectively). The BDE of the H-N bond in HN3 is about 25 kcal/mol lower than that in Ph2C-NH, despite the apparent similarities in hybridization. The acidities of the H-N bonds in acetamide, benzamide, and urea are 2.2, 4.6, and 2.2 kcal/mol higher than those of the H-N bonds in acetamidine, benzamidine, and guanidine, respectively, and their BDEs are 6, 5, and 7 kcal/mol higher. The acidities of the H-N bonds in thioacetamide, thiobenzamide, and thiourea are 9.6, 8.8, and 8.1 kcal/mol higher than those of the H-N bonds in acetamide, benzamide, and urea, respectively, and their BDEs are 17,16, and 18 kcal/mol lower. The 6 kcal/mol lower BDEs for the H-N bonds in acetamidine and benzamidine than in ammonia point to the presence of resonance energy in HN.C(R)=NH radicals in contrast to its near absence in HN.C(R)=O radicals.
- Bordwell, Frederick G.,Ji, Guo-Zhen
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p. 8398 - 8401
(2007/10/02)
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