Danuta Drozdowska

Title : The new benzamide derivatives as potential dementia drugs - synthesis, biological activity and molecular docking study

Abstract:

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

Biography:

Dr. Drozdowska studied Chemistry at Warsaw University, Poland and graduated with an MS in 1989. She then joined the research group of Organic Chemistry, Medical University of Bialystok, Poland. She received her Ph.D. degree in 1999 at the Medical University of Lublin, Poland and her habilitation in 2012 at the Medical University of Lodz, Poland. After that, she obtained the position of an Associate Professor at the Department of Organic Chemistry at the Medical University of Bialystok, Poland. She has published about 50 research articles in SCI(E) journals and promoted four doctors of pharmaceutical sciences as well as close to thirty master's theses.