Functional observational battery (FOB) tests using caffeine and chlorpromazine hydrochloride in sprague-dawley rats.

Caffeine is believed to exert its therapeutic effects by acting as a nonselective, competitive antagonist of adenosine receptors. Chlorpromazine, a phenothiazine, is a classic psychotropic mediator extensively used in the clinical administration of psychotic disorders. This study aimed to validate the procedures used for performing Functional Observational Battery (FOB) tests, to demonstrate the proficiency and interobserver reliability during the FOB tests and also to assess effect on neurobehavioral parameters using positive controls in rats.

SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB.

SARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to long-lasting lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses, which can cause systemic complications.

Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization.

A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.

2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

Water-soluble prodrugs of an Aurora kinase inhibitor.

Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.

Discovery of a potent and selective aurora kinase inhibitor.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition.

Tethering identifies fragment that yields potent inhibitors of human caspase-1.

Disulfide Tethering was applied to the active site of human caspase-1, resulting in the discovery of a novel, tricyclic molecular fragment that selectively binds in S4. This fragment was developed into a class of potent inhibitors of human caspase-1. Several key analogues determined the optimal distance of the tricycle from the catalytic residues, the relative importance of various features of the tricycle, and the importance of the linker.

Chemoselective arylamidine cyclizations: mild formation of 2-arylimidazole-4-carboxylic acids.

A versatile, one-pot synthesis of 2-arylimidazole-4-carboxylic acids from arylamidines and methyl-2-chloroacetoacetate is described. The transformation is chemoselective, and reaction conditions are mild. Moreover, the flexibility of the strategy offers rapid access to two important classes of biaryl compounds, both 2-arylimidazoles and 2-arylpyrimidines, depending simply upon solvent and base selection.

Design and synthesis of dimeric heparinoid mimetics.

Synthetic oligosaccharide constructs exhibiting tailored and well-defined heparan sulfate (HS) like sequences offer the potential to modulate dynamic HS-dependent biomolecular recognition processes. We report an efficient strategy for the generation of HS-like fragments [GlcA-beta-(1,4)-GlcNAc] and related dimerized (gemini) disaccharides (4a and 4b) via n-pentenyl glycoside formation. When a convergent synthetic approach was utilized, construction of target molecules was achieved through a combination of chemoselective protection/deprotection protocols, imidate and n-pentenyl glycosylations, and functional group manipulations followed by ozonolysis and reductive amination.

Glycosaminoglycan-mimetic biomaterials. 3. Glycopolymers prepared from alkene-derivatized mono- and disaccharide-based glycomonomers.

Mono- and disaccharide-containing glycopolymers were synthesized by two different free-radical processes, and their ability to act as heparan sulfate glycomimetics in promoting the binding of Fibroblast Growth Factor-2 (FGF-2) to its receptor (FGFR-1) was evaluated using an in vitro cell-based assay. Cyanoxyl (*OC triple bond N)-mediated polymerization of acrylamide with alkene-derivatized mono- and disaccharides including sulfated or nonsulfated N-acetyl-D-glucosamine is described. The results of this approach are compared to those obtained via the classical ammonium peroxodisulfate (APS)/N,N,N',N'-tetramethylethylenediamine (TMEDA) initiating system and confirm the capacity of cyanoxyl-mediated polymerization to generate a variety of glycopolymers with high saccharide contents and low polydispersity indexes.

Glycosaminoglycan mimetic biomaterials. 4. Synthesis of sulfated lactose-based glycopolymers that exhibit anticoagulant activity.

Cyanoxyl persistent radicals can be used as chain-growth moderators of the statistical copolymerization of a variety of monomers. We report herein the preparation of fully sulfated lactose-based glycopolymers by cyanoxyl (.OC[triple bond]N)-mediated free-radical polymerization of acrylamide derivatized glycomonomers in good yield (60-80%) and low polydispersity (1.