6725-13-9Relevant articles and documents
Inhibitors of bacterial RNA polymerase transcription complex
Bhadbhade, Mohan,Black, David StC,Cain, Amy,Dawson, Catherine,Dinh, Hue,Griffith, Renate,Kumar, Naresh,Lewis, Peter,Miller, Michael,Wenholz, Daniel S.
supporting information, (2021/11/22)
A series of hybrid compounds that incorporated anthranilic acid with activated 1H-indoles through a glyoxylamide linker were designed to target bacterial RNA polymerase holoenzyme formation using computational docking. Synthesis, in vitro transcription inhibition assays, and biological testing of the hybrids identified a range of potent anti-transcription inhibitors with activity against a range of pathogenic bacteria with MICs as low as 3.1 μM. A structure activity relationship study identified the key structural components necessary for inhibition of both bacterial growth and transcription. Correlation of in vitro transcription inhibition activity with in vivo mechanism of action was established using fluorescence microscopy and resistance passaging using Gram-positive bacteria showed no resistance development over 30 days. Furthermore, no toxicity was observed from the compounds in a wax moth larvae model, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action.
Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors
?qvist, Johan,Agalo, Faith,Engen, Karin,Gutiérrez-de-Terán, Hugo,Hallberg, Mathias,Jensen, Annika Jenmalm,Konda, Vivek,Larhed, Mats,Lundb?ck, Thomas,Rosenstr?m, Ulrika,Vanga, Sudarsana Reddy
, p. 325 - 337 (2020/04/07)
Insulin-regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non-peptide IRAP inhibitors derived from a spiro-oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)-promoted three-component reaction, or by a two-step one-pot procedure. For decoration of the oxindole ring system, rapid MW-assisted Suzuki-Miyaura cross-couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S-configuration of the spiro-oxindole dihydroquinazolinones accounts for the inhibition of IRAP.
Thioxo-dihydroquinazolin-one Compounds as Novel Inhibitors of Myeloperoxidase
Li, Yang,Ganesh, Thota,Diebold, Becky A,Zhu, Yerun,McCoy, James W,Smith, Susan M. E,Sun, Aiming,Lambeth, J. David
supporting information, p. 1047 - 1052 (2015/10/20)
Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinsons and Alzheimers. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this class of compounds inhibits MPO with IC50 values as low as 100 nM. Representative compounds showed partially reversible inhibition that was competitive with respect to Amplex Red substrate and did not result in the accumulation of MPO Compound II. Members of this group show promise for therapeutic development for the treatment of diseases in which inflammation plays a pathogenic role.
Neutral, acidic, and basic derivatives of anthranilamide that confer different formal charge to reducing oligosaccharides
Locke, Darren,Bevans, Carville G.,Wang, Lai-Xi,Zhang, Ye,Harris, Andrew L.,Lee, Yuan C.
, p. 221 - 231 (2007/10/03)
To facilitate the use of oligosaccharides as analytical tools in biological studies, we have designed, synthesized, and conjugated to maltosaccharides a novel series of homologous small fluorescent moieties that differ in formal charge. These moieties are
Synthesis and in vitro study of platelet antiaggregant activity of some 4-quinazolinone derivatives
Gravier,Dupin,Casadebaig,Hou,Boisseau,Bernard
, p. 91 - 94 (2007/10/02)
Some new 4-quinazolinones were prepared. Their antiplatelet activity was evaluated in vitro with respect to aggregation induced by ADP, collagen, arachidonic acid and the platelet serotonin release reaction. Most molecules showed an inhibiting power similar to that of acetylsalicylic acid under the same conditions, and even greater when aggregation was induced by ADP. Reduction of the 4-quinazolinone derivatives to their 1,2,3,4-tetrahydroquinazoline homologues produced an increase in platelet inhibitory action except when ADP is the inductor.
