- Synthesis of a Series of Diaminoindoles
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A selection of 3,4-diaminoindoles were required for a recent drug discovery project. To this end, a 10-step synthesis was developed from 4-nitroindole. This synthesis was subsequently adapted and used to synthesize 3,5-; 3,6-; and 3,7-diaminoindoles from
- Martin, James S.,Mackenzie, Claire J.,Gilbert, Ian H.
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p. 11333 - 11340
(2021/09/02)
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- Design and synthesis of indoleamine 2,3-dioxygenase 1 inhibitors and evaluation of their use as anti-tumor agents
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Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole or phenylimidazole scaffolds to improve binding to IDO1. The compounds were synthesized and their inhibitory activities against IDO1 and tryptophan 2,3-dioxygenase were evaluated. The cytotoxicities of the compounds against two tumor cell lines were also determined. Two compounds with a phenylimidazole scaffold (DX-03-12 and DX-03-13) showed potent IDO1 inhibition with IC50 values of 0.3–0.5 μM. These two IDO1 inhibitors showed low cell cytotoxicity, which indicated that they may exert their anti-tumor effect via immune modulation. Compound DX-03-12 was investigated further by determining the in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that DX-03-12 had satisfactory properties in mice, with rapid absorption, moderate plasma clearance (~36% of hepatic blood flow), acceptable half-life (~4.6 h), and high oral bioavailability (~96%). Daily oral administration of 60 mg/kg of compound DX-03-12 decreased tumor growth by 72.2% after 19 days in a mouse melanoma cell B16-F10 xenograft model compared with the untreated control. Moreover, there was no obvious weight loss in DX-03-12-treated mice. In conclusion, compound DX-03-12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.
- Wen, Hui,Liu, Yuke,Wang, Shufang,Wang, Ting,Zhang, Gang,Chen, Xiaoguang,Li, Yan,Cui, Huaqing,Lai, Fangfang,Sheng, Li
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- AMINO COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
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Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R12 or R13 on the A group is an amino substituent (R32) are provided. The inhibitors of Factor D described herein reduce the excessive activation of complement.
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Paragraph 0584; 0585; 0586
(2017/03/14)
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- Efficient Synthesis and Biological Activity of Novel Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors
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A series of novel indole derivatives were synthesized as potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase. Among those, compound 10b demonstrated the highest growth inhibition rate of 66.7% against the VEGFR-2 tyrosine kinase at 10 μM which indicates that indole-benzothiazole might be the favorable structure. The binding mode of compound 10b with VEGFR-2 tyrosine kinase was evaluated by molecular docking.
- Zhang,Xu,Wang,Kang
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p. 3006 - 3016
(2018/02/21)
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- ANTIBACTERIAL THERAPEUTICS AND PROPHYLACTICS
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The present disclosure relates generally to novel molecules, compositions, and formulations for treatment of bacterial infections in general and more specifically to bacterial infections with antibiotic resistant pathogens.
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Paragraph 00363
(2017/02/24)
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- Electrophilicity and nucleophilicity of commonly used aldehydes
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The present approach for determining the electrophilicity (E) and nucleophilicity (N) of aldehydes includes a kinetic study of KMNO4 oxidation and NaBH4 reduction of aldehydes. A transition state analysis of the KMNO4 promoted aldehyde oxidation reaction has been performed, which shows a very good correlation with experimental results. The validity of the experimental method has been tested using the experimental activation parameters of the two reactions. The utility of the present approach is further demonstrated by the theoretical versus experimental relationship, which provides easy access to E and N values for various aldehydes and offers an at-a-glance assessment of the chemical reactivity of aldehydes in various reactions. the Partner Organisations 2014.
- Pratihar, Sanjay
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p. 5781 - 5788
(2014/07/22)
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- Identification of small-molecule enhancers of arginine methylation catalyzed by coactivator-associated arginine methyltransferase 1
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Arginine methylation is a common post-translational modification that is crucial in modulating gene expression at multiple critical levels. The arginine methyltransferases (PRMTs) are envisaged as promising druggable targets, but their role in physiological and pathological pathways is far from being clear due to the limited number of modulators reported to date. In this effort, enzyme activators can be invaluable tools useful as gain-of-function reagents to interrogate the biological roles in cells and in vivo of PRMTs. Yet the identification of such molecules is rarely pursued. Herein we describe a series of aryl ureido acetamido indole carboxylates (dubbed "uracandolates"), able to increase the methylation of histone (H3) or nonhistone (polyadenylate-binding protein 1, PABP1) substrates induced by coactivator-associated arginine methyltransferase 1 (CARM1), both in in vitro and cellular settings. To the best of our knowledge, this is the first report of compounds acting as CARM1 activators.
- Castellano, Sabrina,Spannhoff, Astrid,Milite, Ciro,Dal Piaz, Fabrizio,Cheng, Donghang,Tosco, Alessandra,Viviano, Monica,Yamani, Abdellah,Cianciulli, Agostino,Sala, Marina,Cura, Vincent,Cavarelli, Jean,Novellino, Ettore,Mai, Antonello,Bedford, Mark T.,Sbardella, Gianluca
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supporting information
p. 9875 - 9890
(2013/01/16)
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- NEW SUBSTITUTED ARYLSULPHONYLGLYCINES, THE PREPARATION THEREOF AND THE USE THEREOF AS PHARMACEUTICAL COMPOSITIONS
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The present invention relates to substituted arylsulphonylglycines of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof, which have valuable pharmacological properties, particularly the suppression of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1 ), and their use as pharmaceutical compositions.
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Page/Page column 116
(2008/12/07)
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- ANTIPARASITIC COMPOUNDS AND COMPOSITIONS
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Disclosed is use of a compound having a structure according to general formula (I) defined below, in the manufacture of a medicament to treat and/or prevent a parasitic infection or infestation in a mammalian subject wherein X1 = N or CH or C=O (X2 = NH) or C=S (X2 = NH) or C-OR1 or C-halogen or C-azide; X2 = N or CR1 or C-halogen or CS(O)nR1 where n = 0-2 or a (C)m linker where m = 1-3 between X2 and X6 or C-X5X6 (in which case X5X6 at C6 (purine numbering) is replaced by H or NHR1 or O or OR1 or S or SR1); X3 = N or CH or C-NO2; X4 = N or CH or C-NO2 or C-NR1R2 or an amidine derivative or a guanidinium derivative; X5 = O or NR1 or CR1R2; X6 = OR1 or O-acyl or 0-S(O)nR1 or NR1R2 or NH-acyl or N(Acyl)2 or NH-OS(O)2R1 or NH-S(O)nR1 where n = 0-2 or a hydrazone derivative or an oxime derivative, but if X5 = O, X6 cannot = O or X5X6 is an amidine or an N-substituted pyridine or substituted guanidine; Y = H or NH2 or NR1R2 or -O (X3 = NH) or OR1 or F or Cl or Br or I or CR1R2R3 or S(O)nR1 where n = 0-2 or azide or X5X6 (in which case X5X6 at C6 (purine numbering) is replaced by H or NHR1 or O or OR1 or S or SR1); R1, R2, R3 are independently selected from the group consisting of H or (optionally substituted), alkyl, alkenyl or alkynyl or aryl or aralkyl where the substituents may be selected from H, OH, NH2, halogen, N3, CN, CHO, COOR', C0NR'2, OR, NE'2, SR', NR'NR'2, NR'OR', NO2 and R' is alkyl, alkenyl, alkynyl, aralkyl, acyl, sulfonyl; Z = H or substituted (alkyl or alkenyl or alkynyl or aralkyl) or a sugar derivative of general formula (II) in the β-configuration where: B is the nucleobase from Formula (I); X7 = CH2 or O or NR1 or S; R4 = H or OH or OR1 or halogen or azide or a phosphate derivative; R5 = H or F or CH3; R6 = H or OH or OR1 or halogen or azide or a phosphate derivative; and R7 = H or halogen or R1 or a derivative of an amino acid or PO3H2 or P2O6H3 or P3O9H4 or a methylene derivative of P2O6H3 or P3O9H4 or a masked phosphate or a phosphonate derivative (5'-O replaced with CH2).
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Page/Page column 44
(2010/11/29)
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- Effect of a hydrogen bonding carboxamide group on universal bases
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A number of aromatic universal base analogues have been described in the literature, but most are non-hydrogen bonding. We have examined the effect of introducing hydrogen bonding carboxamide groups onto the pyrrole ring of 5-nitroindole. The modified ana
- Too, Kathleen,Brown, Daniel M.,Holliger, Philipp,Loakes, David
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p. 899 - 911
(2008/02/03)
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- Novel 5-HT3 antagonists: Indol-3-ylspiro(azabicycloalkane-3,5'(4'H)- oxazoles)
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The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.
- Swain,Baker,Kneen,Herbert,Moseley,Saunders,Seward,Stevenson,Beer,Stanton,Watling,Ball
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p. 1019 - 1031
(2007/10/02)
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- Spirocyclic compounds incorporating five-membered rings with two heteroatoms for treating psychotic disorders, etc.
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The present invention provides a compound of formula I or a salt or prodrug thereof: STR1 wherein the dotted line represents an optional chemical bond in one of the two possible positions; A represents a group of formula II: STR2 in which R1 represents hydrogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, benzyloxy, hydroxy (C1-6)alkyl, halogen, amino, cyano, nitro, --CONR6 R7 or --SO2 NR6 R7, in which R6 and R7 independently represent hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; R2 represents hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or C1-6 alkylcarbonyl; V represents nitrogen, --CH or --C--; and W represents oxygen, sulphur or --NR8, in which R8 represents hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; two of X, Y and Z are the same or different and each represents oxygen, sulphur or nitrogen; and the remaining group X, Y or Z is carbon, or Y is carbonyl (C=O); and Q is the residue of an azacyclic or azabicyclic ring system; which compounds are useful in the treatment of psychotic disorders (e.g. schizophrenia and mania); anxiety; alcohol or drug withdrawal or dependence; pain; gastric stasis; gastric dysfunction (such as occurs with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence); migraine, nausea and vomiting; movement disorders; and presenile and senile dementia.
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