Edaravone N-benzyl pyridinium derivatives: BACE-1 inhibition, kinetics and in silico binding pose determination.

BACE-1 plays a pivotal role in the production of ß-amyloid (Aß) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC50 = 44.10 µM - 123.70 µM) and obtained IC50 values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC50 = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC50 of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

Multi-targeted directed ligands for Alzheimer's disease: design of novel lead coumarin conjugates.

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin-morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin-piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 µM and 1 µM, respectively. Molecular modelling studies were conducted with Accelrys® Discovery Studio® V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.

Histamine-3 receptor antagonists reduce superoxide anion generation and lipid peroxidation in rat brain homogenates.

Using a cyanide model to induce neurotoxic effects in rat brain homogenates, we examined the neuroprotective properties of three H3 antagonists, namely clobenpropit, thioperamide and impentamine, and compared them to aspirin, a known neuroprotective agent. Superoxide anion levels and malondialdehyde concentration were assessed using the nitroblue tetrazolium and lipid peroxidation assays. Clobenpropit and thioperamide significantly reduced superoxide anion generation and lipid peroxidation. Impentamine reduced lipid peroxidation at all concentrations used, but only reduced superoxide anion generation at a concentration of 1 mM. In the lipid peroxidation assay, all the drugs compared favourably to aspirin. This study demonstrates the potential of these agents to be neuroprotective by exerting antioxidant effects.

Physical transformation of niclosamide solvates in pharmaceutical suspensions determined by DSC and TG analysis.

This study reports the preparation of four niclosamide solvates and the determination of the stability of the crystal forms in different suspension vehicles by DSC and TG analysis. Thermal analysis showed that the niclosamide solvates were extremely unstable in a PVP-vehicle and rapidly changed to monohydrated crystals. A suspension in propylene glycol was more stable and TG analysis showed that crystal transformation was less rapid. In this vehicle, the crystals transformed to the anhydrate, rather than the monohydrate, since the vehicle was non-aqueous. The TEG-hemisolvate was the most stable in suspension and offered the best possibility of commercial exploitation.

Structure-solubility relationship and thermal decomposition of furosemide.

Furosemide, a high ceiling diuretic, decomposes on heating and is very sparingly soluble in water. The aim of this study was to identify the thermal decomposition product(s) of furosemide and to calculate the activation energy needed for this reaction. This was done to gain a better understanding of the unusually low water solubility of this drug. The main thermal decomposition product was identified by nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared (IR) analysis as 4-chloro-5-sulfamoylanthranilic acid (saluamine), and the activation energy, calculated from thermogravimetric analysis (TGA) measurements, for this reaction was 47.7 (+/- 1.93) kcal/mol. The experimentally measured activation energy was well below the normal 59 +/- 4 kcal/mol needed for the cleavage of the C-N bond to form saluamine. This could possibly be explained by the weakening of the C-N bond through the I-effect of the furane ring and the delocalization of the electrons of the aniline nitrogen in the chlorosulfamoyl benzoic acid entity of furosemide. This decomposition of furosemide indicates the breaking of intramolecular bonds before those of intermolecular bonds (separation of individual furosemide molecules). Strong inter- and intramolecular bonds are a probable cause for the poor water solubility of furosemide because, when some of the inter- and intramolecular bonds that form part of the hydrogen bond network disappeared, as in the structurally related decomposition product saluamine, the aqueous solubility increased.

Structure-activity relationships of polycyclic aromatic amines with calcium channel blocking activity.

8-Benzylamino-8, 11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (1) inhibits the calcium current in L-type calcium channels. A series of nitrobenzylamines (2, 3, 4), methoxybenzylamines (5, 6, 7), methylpyridines (8, 9, 10), and a phenylhydrazine derivative (11) of 8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane was synthesized. By substituting the 8,11-oxapentacyclo-[5.4.0.0(2,6).0(3,10).0(5,9)]undecane skeleton with 3-hydroxyhexacyclo-[6.5.0.0(3,7).0(4,12).0(5,10).0(9,13)]tridec ane (12), 8,13-dioxapentacyclo[6.5.0.0(2,6).0(5,10).0(3,11)]tridecane- 9-one (13), and pentacyclo-[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (14), the effect of the polycyclic skeleton could also be investigated. Increased inhibition of calcium current was observed with aromatic substitution (especially ortho and meta substitution) in the pentacycloundecane series. The calcium channel activities of the methoxy compounds were slightly higher than those of the corresponding nitro compounds while a definite decrease in activity was observed for the phenylhydrazine and aminomethylpyridine derivatives. Increased inhibition of the calcium current was also observed for structures in which the polycyclic 'cages' were enlarged. Structure-activity relationships in this series of compounds therefore appear to be dominated by geometric or steric constraints.

The dissolution and complexing properties of ibuprofen and ketoprofen when mixed with N-methylglucamine.

The objectives of this study were to improve the aqueous dissolution properties of the poorly soluble nonsteroidal anti-inflammatory drugs ibuprofen and ketoprofen and to explore the use of N-methylglucamine (meglumine) to enhance the dissolution properties of poorly water-soluble drug powders. Changes in both differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) results indicate that possibly complexes were produced between ibuprofen and N-methylglucamine. Similar changes were not observed for equivalent ketoprofen and N-methylglucamine mixtures. The results of solubility and dissolution studies in water at 25 degrees C and 37 degrees C showed that N-methylglucamine, in mixtures and coprecipitates, increased the solubility, intrinsic dissolution, and powder dissolution of ketoprofen and ibuprofen. N-Methylglucamine significantly improved the solubility and dissolution properties of both ibuprofen and ketoprofen even when DSC and XRD behavior did not indicate the formation of complexes.

Enantiomeric resolution of the calcium channel antagonist 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]unde cane (NGP 1-01).

We report the enantiomeric resolution and results of studies designed to probe possible enantiospecific calcium channel activity of 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undec ane (NGP 1-01), a known polycyclic benzylamino calcium channel antagonist. R-(-)-acetylmandeloylchloride was used to generate the two diastereomers which were separated by conventional column-chromatography. Hydrolysis of the separated amide diastereomers was achieved in 10% oxalic acid/dichloromethane with silica gel as catalyst and yielded the resolved enantiomers of NGP 1-01. Enantiomeric purity was assessed by in situ derivatization of the individual enantiomers with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (TAGIT) and HPLC analysis. A standard C18 column was used and the enantiomeric purity was found to be 98.5% and 96.63% for the (+)- and (-)-enantiomer, respectively. The enantiomers exhibited similar activity profiles, for calcium channel antagonism and also did not differ from the racemic mixture, suggesting that NGP 1-01 has very weak or no stereo-selectivity in the calcium channel assay used.