1202193-89-2Relevant academic research and scientific papers
Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties
Eleftheriadis, Nikolaos,Poelman, Hessel,Leus, Niek G.J.,Honrath, Birgit,Neochoritis, Constantinos G.,Dolga, Amalia,D?mling, Alexander,Dekker, Frank J.
, p. 786 - 801 (2016)
The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex?vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in?vitro studies on neuronal HT-22?cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration.
Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis
Thanna, Sandeep,Knudson, Susan E.,Grzegorzewicz, Anna,Kapil, Sunayana,Goins, Christopher M.,Ronning, Donald R.,Jackson, Mary,Slayden, Richard A.,Sucheck, Steven J.
, p. 6119 - 6133 (2016/07/06)
Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.
Cyanoacetamide MCR (III): Three-component Gewald reactions revisited
Wang, Kan,Kim, Dabin,Doemling, Alexander
experimental part, p. 111 - 118 (2010/10/19)
Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Here we describe valuable general protocols for the synthesis of arrays of 2-aminothiophene-3carboxamides from cyanoacetamides, aldehydes or ketones, and sulfur via a Gewald-3CR variation, In many cases the reactions involve a very convenient work up by simple precipitation in water and filtration. More than 40 new products are described, We foresee our protocol and the resulting derivatives to become very valuable to greatly expanding the MCR scaffold space of cyanoacetamide derivatives.
