- Pyrrole-thiazole based push-pull chromophores: An experimental and theoretical approach to structural, spectroscopic and NLO properties of the novel styryl dyes
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Novel push-pull fluorophores constituted by two donors (substituted pyrrole and morpholine) linked to acceptor through thiazole electron spacer have been synthesized. The fluorophores are investigated for linear and non-linear optical properties by UV-VIS absorption and fluorescence spectroscopies, and by means of TD-DFT (B3LYP/6-31G(d)) method, with the aim of elucidating the ability of the morpholine/pyrrole-donor-thiazole-spacer based D-π-A fluorophores as organic NLO materials. The bond length alternation and generalized Mulliken-Hush (GMH) analysis is performed to understand the involvement of the donor in effective transfer of the charge to acceptor. Values of first-order hyperpolarizabilities (βCT or β0), obtained by the solvatochromic method (Lippert Mataga model), and the transition dipole moments (μeg) used to characterize and evaluate the non-linear optical performances of the D-π-A fluorophores in various microenvironments. The D-π-A fluorophores possess good values of βCT or β0 in different organic solvents and hold high thermal stabilities therefore can be used as potential organic NLO materials.
- Thorat, Kishor G.,Sekar, Nagaiyan
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Read Online
- Resonance induced proton transfer leading to NIR emission in coumarin thiazole hybrid dyes: Synthesis and DFT insights
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Two novel coumarin thiazole hybrid dyes (E)-2-(3-(2-(4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-morpholinothiazol-5-yl)vinyl)-5,5-dimethylcyclohex-2-en-1-ylidene)malononitrile (CSI) and (E)-2-(3-(2-(4-(4-methoxy-2-oxo-2H-chromen-3-yl)-2-morpholinothiazol-5-yl)vinyl)-5,5-dimethylcyclohex-2-en-1-ylidene)malononitrile (MeOCSI) were synthesized. CSI exhibits near infrared emission with very large Stokes shift. The dye CSI shows resonance induced excited state intramolecular proton transfer (RI-ESIPT). DFT and TD-DFT calculations clearly support and define the finding.
- Shreykar, Milind R.,Sekar, Nagaiyan
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Read Online
- Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis
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8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay.
- Av-Gay, Yossef,Imming, Peter,Narula, Gagandeep,Richter, Adrian,Rudolph, Ines,Wagner, Christoph,Seidel, Rüdiger W.
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supporting information
(2021/12/27)
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- Imidazo ring PAR4 antagonist and medical applications thereof
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The invention relates to an imidazo ring compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt or ester or solvate thereof. The compound disclosed by the inventioncan be used for preparing medicines for preventing or treating thromboembolic diseases.
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Paragraph 0703; 0705; 0707
(2020/01/12)
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- Agonists for the adenosine A1 receptor with tunable residence time. a case for nonribose 4-amino-6-aryl-5-cyano-2-thiopyrimidines
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We report the synthesis and evaluation of previously unreported 4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human adenosine A 1 receptor (hA1AR) agonists with tunable binding kinetics, this without affecting their nanomolar affinity for the target receptor. They show a very diverse range of kinetic profiles (from 1 min (compound 52) to 1 h (compound 43)), and their structure-affinity relationships (SAR) and structure-kinetics relationships (SKR) were established. When put in perspective with the increasing importance of binding kinetics in drug discovery, these results bring new evidence of the consequences of affinity-only driven selection of drug candidates, that is, the potential elimination of slightly less active compounds that may display preferable binding kinetics.
- Louvel, Julien,Guo, Dong,Agliardi, Marta,Mocking, Tamara A. M.,Kars, Roland,Pham, Tan Phát,Xia, Lizi,De Vries, Henk,Brussee, Johannes,Heitman, Laura H.,Ijzerman, Adriaan P.
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p. 3213 - 3222
(2014/05/20)
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- IMIDAZOTHIADIAZOLE AND IMIDAZOPYRAZINE DERIVATIVES AS PROTEASE ACTIVATED RECEPTOR 4 (PAR4) INHIBITORS FOR TREATING PLATELET AGGREGATION
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The present invention provides thiazole compounds of Formula I wherein W, Y, R0, R2, R4, R5, R6, R7, X1, X2, X3 and X4 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments for treating or preventing thromboembolic disorders.
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Paragraph 00259; 00261
(2013/11/18)
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- Synthesis and characterization of novel yellow azo dyes from 2-morpholin-4-yl-1,3-thiazol-4(5H)-one and study of their azo-hydrazone tautomerism
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Novel yellow azo dyes were synthesized by diazotization of aromatic amines followed by coupling with 2-morpholin-4-yl-1,3-thiazol-4(5H)-one and fully characterized. The geometries of the synthesized dyes for azo and hydrazone tautomeric forms were optimized using B3LYP, CAM-B3LYP and M06 functional and 6-31G(d) and 6-311++G (d,p) basis sets, also their electronic excitation properties were evaluated using density functional theory. The optimized geometries reveal that the hydrazone for is more stable than the azo form. Photophysical properties of the synthesized dyes were evaluated by UV-Visible spectroscopy and compared with computed vertical excitation obtained from TDDFT. The results clearly illustrate existence of dye 8a, 8b and 8c in hydrazone tautomeric form, while 8d exist in both azo as well as hydrazone form. Thermal stabilities were estimated by using thermo gravimetric analysis, and results revels that the synthesized dyes have good thermal stability.
- Umape, Prashant G.,Patil, Vikas S.,Padalkar, Vikas S.,Phatangare, Kiran R.,Gupta, Vinod D.,Thate, Abhinav B.,Sekar, Nagaiyan
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p. 291 - 298
(2013/10/21)
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- Reaction of Ph3P(SCN)2 with further orthohydroxy carboxylic acid systems, including substituted β-keto acids: Synthesis of novel 2-thio-1,3-oxazines and their subsequent transformation with amines
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We now report the first reaction of Ph3P(SCN)2 with 4,6-dihydroxy-5- methylisophthalic acid to give 10-methyl-2,8-dithio-1,3-oxazino-1,3-benzoxazine- 4,6-dione. Also, the enol tautomer has been utilized in the reaction of β-keto acids with Ph3P(SCN)2 to give novel 2-thio-1,3-oxazines. Subsequent reaction of the 2-thio-1,3-oxazines with benzylamine resulted in opening of the oxazine ring and gave novel dibenzylamino-enamides, which could be cyclized to thiouracils. The reaction of 2-thio-1,3-oxazines with morpholine at low temperature led to the production of unstable 2-Mercapto-2-morpholino-1,3- oxazines. 2-Mercapto-2-morpholin-4-yl-2,3,5,6,7,8-hexahydro-4H-1,3-benzoxazin-4- one was observed to lose H2S at room temperature to give 2-morpholin-4-yl-5,6,7, 8-tetrahydro-4H-1,3-benzoxazin-4-one, which was subsequently tested and found to exhibit some antiplatelet activity. Copyright Taylor & Francis Group, LLC.
- Pritchard, Kaylene M.,Al-Rawi, Jasim
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scheme or table
p. 4076 - 4096
(2009/04/11)
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- FUSED THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of 5,6-dihydro-l,3-benzothiazol-7(4H)-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PD kinase enzymes, are accordingly of b.enefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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(2008/06/13)
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- THIAZOLE DERIVATIVES AND USE THEREOF
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The present invention is related to thiazole derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung injuries.
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Page/Page column 99
(2008/06/13)
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- CYSTEINE PROTEASE INHIBITORS
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A compound of the formula (II) wherein one of R1 and R2 is halo and the other is H or halo; R3 is C1-C4 straight or branched chain, optionally fluorinated, alkyl; R4 is H; or R3 together with R4 and the adjoining backbone carbon defines: a spiro-C5-C7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C4 alkyl or C1-C4 haloalkyl; or optionally bridged with a methylene group; or a C4-C6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(=O)2 ; where Ra is H, C1-C4 alkyl or CH3C(=O); R5 is independently selected from H or methyl; E is -C(=O)-, -S(=O)m-, -NR5S(=O)m-, -NR5C(=O)-, -OC(=O)-, R6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle; m is independently 0,1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.
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Page/Page column 91
(2010/02/12)
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- Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K
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We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
- Palmer, James T.,Bryant, Clifford,Wang, Dan-Xiong,Davis, Dana E.,Setti, Eduardo L.,Rydzewski, Robert M.,Venkatraman, Shankar,Tian, Zong-Qiang,Burrill, Leland C.,Mendonca, Rohan V.,Springman, Eric,McCarter, John,Chung, Tobee,Cheung, Harry,Janc, James W.,McGrath, Mary,Somoza, John R.,Enriquez, Philip,Yu, Z. Walter,Strickley, Robert M.,Liu, Liang,Venuti, Michael C.,Percival, M. David,Falgueyret, Jean-Pierre,Prasit, Peppi,Oballa, Renata,Riendeau, Denis,Young, Robert N.,Wesolowski, Gregg,Rodan, Sevgi B.,Johnson, Colena,Kimmel, Donald B.,Rodan, Gideon
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p. 7520 - 7534
(2007/10/03)
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- Selenoureas and thioureas are effective superoxide radical scavengers in vitro
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Oxygen radicals, such as superoxide radicals, embellishing DNA, protein, lipids, etc., and carrying out the obstacle of the function of a cell is known. It depends for the oxidant level in the living body on the balance of a generation system and an elimination system of oxygen radicals, and research which controls an oxidant level in the living body is briskly done by taking in the substance which eliminates an oxygen radical. We investigated scavenging effects of superoxide radicals by selenoureas and thioureas using a highly sensitive and quantitative chemiluminescence method. At 330 nM, five selenoureas and five thioureas scavenged fractions of superoxide radicals (O 2-) ranging from 8.4% to 87.6%. Among five N,N-unsubstituted selenoureas and N,N-unsubstituted thioureas 1-selenocarbamoylpiperidine and 1-thiocarbamoylpyrrolidine were the most effective scavengers. A possibility that selenoureas could use it as a new superoxide anion-scavenging substance from the result of this research became clear.
- Takahashi, Hitoe,Nishina, Atsuyoshi,Fukumoto, Ryo-Hei,Kimura, Hirokazu,Koketsu, Mamoru,Ishihara, Hideharu
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p. 2185 - 2192
(2007/10/03)
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- Synthesis of mono- and N,N-disubstituted thioureas and N-acylthioureas
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1-Benzotriazole-1-carbothioamide (2), prepared from 1-cyanobenzotriazole (1) and hydrogen sulfide, reacts with amines to give thioureas 3a-e. Reactions of (benzotriazol-1-yl)carboximidamides 4a-d,f-j and acyl- 5a-f,i-k or arylaminocarbonyl- 5g,h (benzotri
- Katritzky, Alan R.,Kirichenko, Nataliya,Rogovoy, Boris V.,Kister, Jeremy,Tao, Hui
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p. 1799 - 1805
(2007/10/03)
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- Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy
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The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 μM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
- Kempf, Dale J.,Sham, Hing L.,Marsh, Kennan C.,Flentge, Charles A.,Betebenner, David,Green, Brian E.,McDonald, Edith,Vasavanonda, Sudthida,Saldivar, Ayda,Wideburg, Norman E.,Kati, Warren M.,Ruiz, Lisa,Zhao, Chen,Fino, Lynnmarie,Patterson, Jean,Molla, Akhteruzzaman,Plattner, Jacob J.,Norbeck, Daniel W.
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p. 602 - 617
(2007/10/03)
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- N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety
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We previously reported the identification of (2S)-((2- benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4- yl)ethoxy]phenyl}propanoic acid (2) (PPARγ pK(i) = 8.94, PPARγ pEC50 = 9.47) as a potent and selective PPARγ agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARγ agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2- benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4- yl)ethoxy]phenyl}propionic acid (16) (PPARγ pK(i) = 8.85, PPARγ pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4- {2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}phenyl)propionic acid (24) (PPARγ pK(i) = 8.66, PPARγ pEC50 = 8.89) provided two potent and selective PPARγ agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARγ ligands (PPARγ pK(i)'s 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARγ binding, functional activity, selectivity, and aqueous solubility.
- Collins, Jon L.,Blanchard, Steven G.,Boswell, G. Evan,Charifson, Paul S.,Cobb, Jeff E.,Henke, Brad R.,Hull-Ryde, Emily A.,Kazmierski, Wieslaw M.,Lake, Debra H.,Leesnitzer, Lisa M.,Lehmann, Jürgen,Lenhard, James M.,Orband-Miller, Lisa A.,Gray-Nunez, Yolanda,Parks, Derek J.,Plunkett, Kelli D.,Tong, Wei-Qin
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p. 5037 - 5054
(2007/10/03)
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- Activation of Dithiocarbamate by 2-Halothiazolium Salts
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Activation of dithiocarbamate salts with 2-halo-3-alkyl-4-phenylthiazolium salt and subsequent one-pot nucleophilic reaction with N, S, and O nucleophiles provided substituted thioureas, dithiocarbamates, and thiocarbamates or amides, respectively, under very mild conditions.A useful thiocarbonyl-transfer reaction is also described that consists of activation of imidazolodithiocarbamate and a subsequent one-pot nucleophilic reaction. (Thiocarbonyl)diimidazole is generated in situ.
- Sugimoto, Hirohiko,Makino, Itsuo,Hirai, Kentaro
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p. 2263 - 2267
(2007/10/02)
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- Synthesis of Heterocyclic Compounds via Enamines. Part 8. Acid-catalysed Transformations in 4,4,6-Trimethyl-1,4-Dihydropyrimidine-2(3H)-thione Derivatives and Related Compounds
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1-Substituted 4,4,6-trimethyl-1,4-dihydropyrimidine-2(3H)-thiones (2) on heating in 11M-HCl at 100-110 deg C are converted into the corresponding 2-substituted-amino-4,6,6-trimethyl-6H-1,3-thiazines (4) and/or thioureas.But at 95-100 deg C, Dimroth rearrangement products, e.g. the corresponding 2-substituted-amino-4,4,6-trimethyl-4H-1,3-thiazenes (3) are formed.
- Singh, Harjit,Singh, Paramjit
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p. 1013 - 1018
(2007/10/02)
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