Discovery of novel hybrid tryptamine-rivastigmine molecules as potent AChE and BChE inhibitors exhibiting multifunctional properties for the management of Alzheimer's disease

Contemporary research evidence has corroborated a gradual loss of central cholinergic neurons in Alzheimer's Disease (AD). This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death in the disease. The approved drugs for AD treatment can only offer relief from symptoms without addressing the underlying pathological hallmarks of the disease. To address the limitations associated with rivastigmine (RIV), a marketed drug for AD, a series of tryptamine derivatives was designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. Enzyme inhibition studies identified compounds 6d and 6e as the lead molecules with potent inhibitors against AChE (6d, IC₅₀: 0.99 ± 0.009 nM and 6e IC₅₀: 7.97 ± 0.016 nM and BChE (6d, IC₅₀: 27.79 ± 0.21 nM and 6e, IC₅₀: 0.79 ± 0.005 nM), compared to the marketed drug Riv (AChE, IC₅₀: 6630 ± 0.76 nM, BChE IC₅₀ = 91 ± 0.40 nM). The molecular docking and dynamics studies corroborated the enzyme inhibition studies. The PAMPA assay strongly suggested the BBB crossing ability of the lead molecules. Further, 6d and 6e demonstrated the capability to counteract oxidative stress and Aβ_1-42 in various in-vitro studies. Compound 6e exhibited remarkable radical scavenging activity in the DPPH assay (IC₅₀: 22.91 ± 1.73 μM) compared to rivastigmine (% radical scavenging activity: 3.71 ± 0.09 at 200 μM). Interestingly, 6d and 6e exhibited promising activity in the AD Drosophila model by protecting eye phenotypes from degeneration induced by Aβ_1-42 toxicity and reduced mitochondrial and cellular oxidative stress in this model. Furthermore, upon oral administration, 6d and 6e could reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice at 0.3 and 0.5 mg/kg compared to rivastigmine at 3 mg/kg and were found to have potent ex-vivo anti-ChEs properties, which are correlated with the observed pro-cognitive effects in the Morris Water Maze, likely mediated through the inhibition of both cholinesterases. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group.