Abstract
Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase’s inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound. A LogP assay confirmed that 3e compound fulfills Lipinsky’s rule of five
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and chronic, neurodegenerative disease
Flash chromatography as the purifying technique was performed using silica gel 60, Merck. infrared (IR) spectra were recorded on the Mattson Infinity Series Fourier transform infrared (FT-IR) spectrophotometer, in ATR. 1H NMR spectra were recorded on BrukerAvance III 600 MHz spectrometer
The results demonstrated that compound 3e is a dual AChE and BuChE inhibitor and a promising compound for further development
Summary
Alzheimer’s disease (AD) is the most common form of dementia and chronic, neurodegenerative disease. AD attacks the brain leading to impaired memory, thinking and behavior, mainly among the elderly. AD has been proven to be a multifactorial disease associated with several aspects including low levels of acetylcholine (ACh), formation of β-amyloid (Aβ), hyperphosphorylated tau aggregates, oxidative stress and so on. Genetic studies have shown that dysfunction of Aβ or tau is sufficient to cause dementia. Ongoing molecular research is expected to lead to a true understanding of the disease’s pathogenesis. The neuropathological alterations described above suggest that the target at these factors could create the possible and effective treatment of AD [1,2]
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