Drug repositioning study for alzheimer's disease treatment

Alzheimer's disease is the main cause of dementia and is one of the most deadly, and economically burdensome diseases of this century. Current data indicates that the prevalence of dementia will double in Europe and triple worldwide by 2050. In the early stages of Alzheimer's disease, it has been determined that the spread of tau pathology is triggered by the accumulation of amyloid beta (Aβ), and the disease is dependent on hereditary factors by 60- 80%. Promising pharmacological treatments have reached advanced-stage clinical trials and include anti-Aβ, anti-tau, and anti-inflammatory strategies. However, drug development efforts for Alzheimer's disease have resulted in a very high failure rate of 99.6% between 2002 and 2012 due to the complex nature of Alzheimer's. This negative trend continues today. Therefore, there is still a significant need for treatments that can slow down or prevent the progression of Alzheimer's disease. In recent years, there has been growing interest in the strategy of drug repurposing, which involves discovering new uses for existing drug molecules to treat different diseases. This approach has gained attention, particularly due to the high cost and lengthy time required for traditional drug development. Drug repurposing holds the potential for achieving higher success rates in a shorter time frame, making it a valuable approach for the treatment of Alzheimer's disease. In this thesis study, through an extensive literature review and in silico methods within the framework of drug repositioning strategy, it has been determined that the active ingredients metronidazole and secnidazole, which belong to the nitroimidazole derivative class of antiprotozoal and antibacterial drugs, could be effective against Alzheimer's disease. Furthermore, new derivatives of these drug molecules were designed, synthesized, and their effectiveness on Alzheimer's disease was demonstrated. In the initial stage of the study, eight new derivatives were synthesized using a one-step synthesis method based on metronidazole and secnidazole. The structures of the synthesized molecules were determined using 1H-NMR and 13C-NMR. Subsequently, the compounds' inhibition effects on AChE and BChE were determined based on IC50 and Ki values using the Ellman method. The IC50 values for AChE ranged from 36.47 to 115.50 nM, while for BChE, they ranged from 69.30 to 231.00 nM. The corresponding Ki values were calculated as 52.40-240.80 nM for AChE and 77.82-323.70 nM for BChE. Molecular docking studies were also conducted to illustrate the interactions between the compounds and the active sites of the enzymes.The findings of this study demonstrate that the designed compounds, based on active drug molecules identified through drug repurposing studies, exhibit potent AChE and BChE inhibitory effects and hold promise as potential lead compounds against Alzheimer's disease.