54904-12-0Relevant articles and documents
Dual-Acting Small-Molecule Inhibitors Targeting Mycobacterial DNA Replication
Singh, Meenakshi,Ilic, Stefan,Tam, Benjamin,Ben-Ishay, Yesmin,Sherf, Dror,Pappo, Doron,Akabayov, Barak
, p. 10849 - 10860 (2020)
Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium and a causative agent of tuberculosis (TB), a disease that kills more than 1.5 million people worldwide annually. One of the main reasons for this high mortality rate is the evolution of new Mtb strains that are resistant to available antibiotics. Therefore, new therapeutics for TB are in constant demand. Here, we report the development of small-molecule inhibitors that target two DNA replication enzymes of Mtb, namely DnaG primase and DNA gyrase (Gyr), which share a conserved TOPRIM fold near the inhibitors’ binding site. The molecules were developed on the basis of previously reported inhibitors for T7 DNA primase that bind near the TOPRIM fold. To improve the physicochemical properties of the molecules as well as their inhibitory effect on primase and gyrase, 49 novel compounds have been synthesized as potential drug candidates in three stages of optimization. The last stage of chemical optimization yielded two novel inhibitors for both Mtb DnaG and Gyr that also showed inhibitory activity toward the fast-growing non-pathogenic model Mycobacterium smegmatis (Msmg).
3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17
Baqi, Younis,Pillaiyar, Thanigaimalai,Abdelrahman, Aliaa,Kaufmann, Olesja,Alshaibani, Samer,Rafehi, Muhammad,Ghasimi, Saman,Akkari, Rhalid,Ritter, Kirsten,Simon, Katharina,Spinrath, Andreas,Kostenis, Evi,Zhao, Qiang,K?se, Meryem,Namasivayam, Vigneshwaran,Müller, Christa E.
, p. 8136 - 8154 (2018/08/09)
The orphan receptor GPR17 may be a novel drug target for inflammatory diseases. 3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid (MDL29,951, 1) was previously identified as a moderately potent GPR17 agonist. In the present study, we investigated the structure-activity relationships (SARs) of 1. Substitution of the indole 1-, 5-, or 7-position was detrimental. Only small substituents were tolerated in the 4-position while the 6-position accommodated large lipophilic residues. Among the most potent compounds were 3-(2-carboxyethyl)-1H-indole-2-carboxylic acid derivatives containing the following substituents: 6-phenoxy (26, PSB-1737, EC50 270 nM), 4-fluoro-6-bromo (33, PSB-18422, EC50 27.9 nM), 4-fluoro-6-iodo (35, PSB-18484, EC50 32.1 nM), and 4-chloro-6-hexyloxy (43, PSB-1767, EC50 67.0 nM). (3-(2-Carboxyethyl)-6-hexyloxy-1H-indole-2-carboxylic acid (39, PSB-17183, EC50 115 nM) behaved as a partial agonist. Selected potent compounds tested at human P2Y receptor subtypes showed high selectivity for GPR17. Docking into a homology model of the human GPR17 and molecular dynamic simulation studies rationalized the observed SARs.
Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I
Akladios, Fady N.,Nadvi, Naveed A.,Park, Joohong,Hanrahan, Jane R.,Kapoor, Vimal,Gorrell, Mark D.,Church, W. Bret
, p. 1579 - 1581 (2012/04/04)
Herein we report 6-ethoxy-6-oxo-5-(2-phenylhydrazono) hexanoic acid and 3-(2-carboxyethyl)-1Hindole-2-carboxylic acid derivatives as synthetically accessible leads for human kynurenine aminotransferase-I (KAT-I) inhibitors. In total, 12 compounds were synthesized and their biological activities were determined using the HPLC-UV based KAT-I inhibition assay. Of the 12 compounds synthesized, 10 were found to inhibit human KAT-I and the most active compound was found to be 5-(2-(4-chlorophenyl) hydrazono)-6-ethoxy-6-oxohexanoic acid (9a) with an IC50 of 19.8 lM.
New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents
Menciu, Cecilia,Duflos, Muriel,Fouchard, Fabienne,Le Baut, Guillaume,Emig, Peter,Achterrath, Ute,Szelenyi, Istvan,Nickel, Bernd,Schmidt, Jürgen,Kutscher, Bernhard,Günther, Eckhardt
, p. 638 - 648 (2007/10/03)
A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2- decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3- yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 μM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 μM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 μM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin- induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 μM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.
3-(2-Carboxyindol-3-yl)propionic Acid-Based Antagonists of the N-Methyl-D-aspartic Acid Receptor Associated Glycine Binding Site
Salituro, Francesco G.,Harrison, Boyd L.,Baron, Bruce M.,Nyce, Philip L.,Stewart, Kenneth T.,et al.
, p. 1791 - 1799 (2007/10/02)
A series of substituted 3-(2-carboxyindol-3-yl)propionic acids was synthesized and tested as antagonists for the strychnine-insensitive glycine binding site of the NMDA receptor.Chlorine, and other small electron-withdrawing substituents in the 4- and 6-p
BENZOCONDENSED HEPTAATOMIC HETEROCYCLES AND THEIR DERIVATIVES. VII. SYNTHESIS OF BENZAZEPINES AND BENZAZEPINONES ANALOGUES OF KNOWN ANXIOLYTIC DRUGS
Rossi, Silvano,Micheli, Marcello,Giannotti, Michele,Salvatori, Americo,Peruzzi, Guidubaldo
, p. 365 - 370 (2007/10/02)
Two syntheses are described for a series of benzazepines structurally similar to known anxiolytic drugs.Some of the new molecules are active in the barbiturates-induced sleep potentiation test and possess a negligible acute toxicity.
