Pyranopyrazolotacrines as Nonneurotoxic, Aβ-Anti-Aggregating and Neuroprotective Agents for Alzheimer's Disease

Abstract

Aim: Due to the complex nature of Alzheimer's disease, there is a renewed search for multipotent, nonhepatotoxic tacrines. Results: This paper describes the synthesis and in vitro biological evaluation of eight new racemic 3-methyl-4-aryl-2,4,6,7,8,9-hexahydropyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolin-5-amines (pyranopyrazolotacrines, PPT) as nonhepatotoxic multipotent tacrine analogs. Among these compounds, PPT4 is the less hepatotoxic in the cell viability assay on HepG2 cells, showing a good neuroprotective effect in the decreased cortical neuron viability induced by oligomycin A/rotenone analysis. PPT4 is a selective and good, noncompetitive EeAChE inhibitor, able to completely inhibit the Aβ1–40 aggregation induced by acetylcholinesterase. Conclusion: A new family of nonhepatotoxic showing selective acetylcholinesterase inhibition, permeable tacrine analogs have been discovered for the potential treatment of Alzheimer's disease.

New cyclopentaquinoline hybrids with multifunctional capacities for the treatment of Alzheimer’s disease

“…Alzheimer’s disease is a neurodegenerative, progressive disorder of central nervous system (CNS) that generally affects aged people. It is the most common cause of dementia which makes up 70% of senile dementia 1 . Today there are 47 million people living with dementia worldwide.…”

Five-Membered-Ring-Fused Tacrines as Anti-Alzheimer’s Disease Agents

“…Once more, no clear SAR was evident, although an electron-withdrawing group at C4′, such as nitro (94o), or an electron-donor substituent at C2′, such as methoxy (94f), seemed to afford the best inhibitory capacity. 70 A mechanism underlying the kinetic inhibition of EeAChE by 94f, the least hepatotoxic and most efficacious AChEI, was proposed, indicating that 94f behaved as a noncompetitive inhibitor. This result was confirmed by the statistical analysis of K m and V max tendencies, which clearly demonstrated a significant trend for V max to decrease, whereas K m did not exhibit a statistically significant tendency to increase.…”

“…These results confirmed the observed noncompetitive inhibition mechanism for the inhibition of EeAChE by these pyranopyrazolotacrines. 70 Neuroprotection investigation was carried out with the cocktail oligomycin A (10 M)/rotenone (30 M) as a toxic insult that blocks mitochondrial electron transport chain complexes I and V, thereby inducing cell death by oxidative stress in a concentration-dependent manner.…”

“…While tacrine manifested toxic effects (>25-60% at 25-100 M), derivatives 94c-p proved to be nonneurotoxic between 1 and 50 M. 70 Molecular modeling studies were also implemented through docking simulations with AutoDockVina to elucidate the nature and spatial location of the key interactions of the (R)-and (S)-enantiomers of 94o, which had been selected as the most potent EeAChEI. The orientations of both tautomers are similar, as they bind to the PAS through strong hydrogen-bonding interactions and - stacking interactions.…”

Therapeutic Potential of Multifunctional Tacrine Analogues

“…They found that the most effective compound 1d bearing a 3,4-dimethoxyphenyl group was more active than the reference drug tacrine and significantly protected neurons against oxidative stress, as potent as quercetin at low concentrations. A similar tacrine analogs family has been independently and almost simultaneously described by Marco-Contelles’ team [131].…”