Title : The new benzamide derivatives as potential dementia drugs - synthesis, biological activity and molecular docking study
Designing, synthesize and developing of novel bioactive molecules is the crucial role of medicinal chemistry. The concept of drug design and development, called multi-target directed ligand (MTDL), multiple ligand strategy (MLS) or designed multiple ligands (DMLs), is an innovative approach in the search for drugs, especially for diseases with no effective therapy. Alzheimer’s disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. Such a disorder is a neurodegenerative disease characterised by progressive memory loss and other cognitive deficits, namely Alzheimer's disease (AD). Among the many different AD treatments, cholinesterases still remain key biological targets in AD therapy. The second most common therapeutic target is to affect β-amyloid aggregation by inhibiting β-secretase (BACE1), which initiates its production. Aggregation is believed to be one of the main causes of Alzheimer's disease and therefore its inhibition may modify the course of the disease. Our paper presents the synthesis of multifunctional ligands, their inhibitory activity against both cholinesterase and secretase. and molecular docking study. Using classical procedures, we obtained eleven benzamide molecules and all of them showed significant AChE and BACE1 inhibition. Ellman’s colorimetric method was used to determine the AChE inhibitory activity and fluorescence resonance energy transfer (FRET) method to carry out the BACE1 inhibitory activity studies. The most active against both AChE was N,N'-(1,4-phenylene)bis(3-methoxybenzamide) with an inhibitory concentration of AChE IC50 = 0.056 µM, while the IC50 for donepezil was 0.046 µM. This compound was the most active also against BACE1 enzyme. The IC50 value for it was 9.01 µM compared to quercetine with IC50 = 4.89 µM. The molecular docking studies elucidate how and where ligands interact with enzymes and allow the design of compounds with the most optimal structure for subsequent research.
Audience Take Away Notes:
- The audience will be able to broaden their knowledge of the structure-activity relationships and mechanisms of action of new active compounds
- This research may inspire other researchers to extend their research into new directions, e.g. synthetic chemists to broadly investigate the activity of new substances
- The results presented enriched the knowledge of pharmacotherapy options for Alzheimer's disease