A5004794700- Synthesis and Biological Evaluation
- Synthesis and biological activity
- Synthesis and Reactions of Organic Compounds
- Chronic Lymphocytic Leukemia Research
- Synthesis and Characterization of Heterocyclic Compounds
- Synthesis of Organic Compounds
- Synthesis of heterocyclic compounds
- Enzyme Structure and Function
- PI3K/AKT/mTOR signaling in cancer
- Multicomponent Synthesis of Heterocycles
- Crystallization and Solubility Studies
- Biochemical and Molecular Research
- Chemical Synthesis and Analysis
- Advanced biosensing and bioanalysis techniques
- X-ray Diffraction in Crystallography
- Microwave-Assisted Synthesis and Applications
- Catalytic C–H Functionalization Methods
- Escherichia coli research studies
- Click Chemistry and Applications
- Drug Transport and Resistance Mechanisms
- DNA and Nucleic Acid Chemistry
- Phenothiazines and Benzothiazines Synthesis and Activities
- Photochromic and Fluorescence Chemistry
- Synthesis and Catalytic Reactions
- Histone Deacetylase Inhibitors Research
AstraZeneca (Sweden)
2012-2024
Pharmaron (United Kingdom)
2017
AstraZeneca (Brazil)
2017
Institute of Medicinal Plant Development
2017
Bioscience Research
2017
University of Gothenburg
2009-2016
Umeå University
2004-2008
A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone–usher pathway in Gram-negative pathogens. The activity a family bicyclic 2-pyridones, termed pilicides, evaluated two different pilus systems uropathogenic Escherichia coli . Hemagglutination mediated either type 1 or P pili, adherence bladder cells, biofilm formation were all reduced ≈90% laboratory clinical E. strains. structure...
Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family mainly targeting cytosolic nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 to regulate cell proliferation, metastasis, invasion, mitosis in tumors. We describe identification characterization series 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) selective nonhydroxamic acid HDAC6 inhibitors. By comparing structure-activity relationships performing quantum mechanical calculations catalytic...
A base-promoted condensation between 2-hydroxyacetophenones and aliphatic aldehydes has been studied. The reaction optimized to afford 2-alkyl-substituted 4-chromanones in an efficient manner using microwave heating. Performing the diisopropylamine EtOH at 170 degrees C for 1 h gave moderate high yields (43-88%). could be further converted into highly functionalized 2,3,6,8-tetrasubstituted chromones which a 3-substituent (acetate, amine, or bromine) was introduced via straightforward...
An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar heterocyclic carboxylic acid bioisosteres is described. The sulfonimidamide ring system could be prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester amino acids. By varying the acid, range different C-3 prepared. compounds further derivatized using standard cross-coupling reactions to yield highly excellent yields. physicochemical properties final were examined...
In this paper, we describe the discovery and optimization of a new chemotype isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency physicochemical properties could be improved to give compounds such as 15, which is potent remarkably inhibitor with ADME suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition LPS-induced airway neutrophilia rats when administered orally.
Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure–activity relationships that led to discovery highly potent dual PI3Kγδ inhibitors. We explored changes in two positions molecules, including macrocyclization, but ultimately identified a simpler series with desired potency profile had suitable physicochemical properties for inhalation. were able demonstrate efficacy rat ovalbumin challenge model allergic asthma and cells derived asthmatic...
G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 have therapeutic potential, there currently >1000 known ligands. Despite this, only two ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic studied their interactions with G4s (e.g., from the c-MYC, c-KIT, BCL-2 promoters) using biochemical assays. We further effect of selected compounds on cell...
Polycyclic ring-fused 2-pyridones (5a-e and 9a-e) have been prepared via a microwave-assisted acyl-ketene imine cyclocondensation. Starting from 3,4-dihydroisoquinolines (4a-b) or 3,4-dihydroharman (8), fused could be in one-step procedure. By using either Meldrum's acid derivatives (1a-d) 1,3-dioxine-4-ones (7a-b) as sources, mono- disubstitution of the 2-pyridone ring accomplished. As an application method, formal synthesis indole alkaloid sempervilam was performed.
A novel combination of SmI(2), KHMDS, and TsCN can be utilized to introduce a cyano group into structurally diverse highly sensitive 2-alkyl-chroman-4-ones. Subsequent oxidation allows the formed 2-alkyl-3-cyanochromones isolated in yields ranging from 49 77%. In addition, alpha-bromoketones esters were found undergo equally effective alpha-cyanation.
By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene were introduced via a cyanodehalogenation followed by borane dimethyl sulfide reduction of the afforded nitrile. In both these transformations, microwave irradiation proved be superior traditional and primary amines obtained good overall yields (55-58% over three steps). To incorporate...
PI3Kδ is a lipid kinase that believed to be important in the migration and activation of cells immune system. Inhibition hypothesized provide powerful yet selective immunomodulatory effect may beneficial for treatment conditions such as asthma or rheumatoid arthritis. In this work, we describe identification inhibitors based on thiazolopyridone core structure their subsequent optimization inhalation. The initially identified compound (13) had good potency isoform selectivity but was not...
This study aims to deepen the knowledge of current state rational G4-ligand design through and synthesis a novel set compounds based on indoles, quinolines, benzofurans their comparisons with well-known G4-ligands. resulted in synthetic methods G4-ligands that bind stabilize G4 DNA high selectivity. Furthermore, corroborates previous studies adds deeper explanations why a) macrocycles offer advantages terms G4-binding -selectivity, b) molecular pre-organization is key importance development...
Optically active Δ2-thiazolines 4 were previously reported to react with acyl Meldrum's acid derivatives 5 under acidic conditions (HCl (g) in benzene) stereoselectively give 6-acylpenams 1. Recently we have discovered that the structure elucidation of these compounds was incorrect. Thus, report new data showing instead β-lactams, optically isomers 3R,9R-1,3-oxazinones 3a−g are obtained 38−93% yields.
To further facilitate the discovery of cysteine reactive covalent inhibitors, there is a need to develop new groups beyond traditional acrylamide-type warheads. Herein we describe design and synthesis EGFR inhibitors that use vinylpyridine as group. Structure-based identified quinazoline-containing 6 starting point. Further modifications focused on reducing reactivity resulted in substituted vinyl compound 12, which shows high potency good kinase selectivity, well significantly reduced...
Adherence of uropathogenic Escherichia coli to host tissue is mediated by pili, which are hair-like protein structures extending from the outer cell membrane bacterium. The chaperones FimC and PapD key components in pilus assembly since they catalyse folding subunits that incorporated type 1 P respectively, also transport across periplasmic space. Recently, compounds inhibit biogenesis interfere with chaperone–subunit interactions have been discovered termed pilicides. In this paper NMR...
The salt-inducible kinases (SIKs) 1-3, belonging to the AMPK-related kinase family, serve as master regulators orchestrating a diverse set of physiological processes such metabolism, bone formation, immune response, oncogenesis and cardiac rhythm. Owing its key regulatory role, SIK have emerged compelling targets for pharmacological intervention across indications. Therefore, there is interest in developing inhibitors with defined selectivity profiles both further dissect downstream biology...
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