Acetylcholinesterase Inhibitors: Structure Based Design, Synthesis, Pharmacophore Modeling, and Virtual Screening

• Published in: Journal of chemical information and modeling 2013-08, Vol.53 (8), p.2033-2046
• Main Authors: Valasani, Koteswara Rao, Chaney, Michael O, Day, Victor W, ShiDu Yan, Shirley
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Alzheimer's disease; Applied sciences; Biological and medical sciences; Chemical compounds; Chemistry; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - metabolism; Cholinesterase Inhibitors - pharmacokinetics; Cholinesterase Inhibitors - pharmacology; Computer science; control theory; systems; Correlation analysis; Crystallization; Data processing. List processing. Character string processing; Drug Design; Drug Evaluation, Preclinical; Exact sciences and technology; General and physical chemistry; General pharmacology; General. Nomenclature, chemical documentation, computer chemistry; Humans; Indans - chemical synthesis; Indans - metabolism; Indans - pharmacokinetics; Indans - pharmacology; Medical sciences; Memory organisation. Data processing; Metabolism; Molecular Docking Simulation; Molecules; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - metabolism; Piperidines - pharmacokinetics; Piperidines - pharmacology; Protein Conformation; Quantitative Structure-Activity Relationship; Simulation; Single crystals; Software; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; User-Computer Interface
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci400196z

Acetylcholinesterase (AChE) is a main drug target, and its inhibitors have demonstrated functionality in the symptomatic treatment of Alzheimer’s disease (AD). In this study, a series of novel AChE inhibitors were designed and their inhibitory activity was evaluated with 2D quantitative structure–activity relationship (QSAR) studies using a training set of 20 known compounds for which IC50 values had previously been determined. The QSAR model was calculated based on seven unique descriptors. Model validation was determined by predicting IC50 values for a test set of 20 independent compounds with measured IC50 values. A correlation analysis was carried out comparing the statistics of the measured IC50 values with predicted ones. These selectivity-determining descriptors were interpreted graphically in terms of principal component analyses (PCA). A 3D pharmacophore model was also created based on the activity of the training set. In addition, absorption, distribution, metabolism, and excretion (ADME) descriptors were also determined to evaluate their pharmacokinetic properties. Finally, molecular docking of these novel molecules into the AChE binding domain indicated that three molecules (6c, 7c, and 7h) should have significantly higher affinities and solvation energies than the known standard drug donepezil. The docking studies of 2H-thiazolo[3,2-a]pyrimidines (6a–6j) and 5H-thiazolo[3,2-a] pyrimidines (7a–7j) with human AChE have demonstrated that these ligands bind to the dual sites of the enzyme. Simple and ecofriendly syntheses and diastereomeric crystallizations of 2H-thiazolo [3,2-a]pyrimidines and 5H-thiazolo[3,2-a] pyrimidines are described. The solid-state structures for the HBr salts of compounds 6a, 6e, 7a, and 7i have been determined using single-crystal X-ray diffraction techniques, and X-ray powder patterns were measured for the bulk solid remaining after solvent was removed from solutions containing 6a and 7a. These studies provide valuable insight for designing more potent and selective inhibitors for the treatment of AD.