Acylhydrazones derived from isonicotinic acid: Synthesis, characterization, and evaluation against Alzheimer's disease biomarkers

Abstract

Acylhydrazones have garnered attention as a promising structural motif due to their capacity to establish hydrogen bonds and interact effectively with biomolecular targets. In this study, we synthesized ten distinct acylhydrazones using the carbohydrazide of isonicotinic acid (INH) in combination with various substituted aromatic aldehydes. The compounds were obtained with moderate chemical yields, in the range of 28 to 82 %. Following thorough spectroscopic characterization, we proceeded to investigate the impact of the synthesized compounds on key biochemical indicators associated with Alzheimer's disease. We examined the inhibition of acetylcholinesterase (AChE) and β-secretase (BACE-1) through Ellman's colorimetric assay and FRET assay, respectively. The formation of Aβ fibrils was assessed using Thioflavin T fluorescence emission, while the compounds' ability to scavenge free radicals was evaluated using the DPPH method. Notably, the most of compounds demonstrated inhibitory effects on AChE, with the acylhydrazone derived from 3,5-difluorobenzaldehyde and INH displaying the highest potency. Among the array of tested compounds, the derivative sourced from 4-trifluoromethylbenzaldehyde exhibited AChE and BACE-1 inhibitory activity, with IC50 values of 2.98 and 63.9 µM, respectively. This compound also has an effect on inhibiting the formation of Aβ fibrils (IC50 = 17.1 µM) and DPPH radical scavenging activity in 88 %. Physicochemical and pharmacokinetic properties were in silico calculated using SwissADME software and all compounds were predicted to have good oral bioavailability.