Similarity-Based Virtual Screening to Find Antituberculosis Agents Based on Novel Scaffolds: Design, Syntheses and Pharmacological Assays.

A method to identify molecular scaffolds potentially active against the Mycobacterium tuberculosis complex (MTBC) is developed. A set of structurally heterogeneous agents against MTBC was used to obtain a mathematical model based on topological descriptors. This model was statistically validated through a Leave-n-Out test. It successfully discriminated between active or inactive compounds over 86% in database sets. It was also useful to select new potential antituberculosis compounds in external databases. The selection of new substituted pyrimidines, pyrimidones and triazolo[1,5-a]pyrimidines was particularly interesting because these structures could provide new scaffolds in this field. The seven selected candidates were synthesized and six of them showed activity in vitro.

Combined Structure and Ligand-Based Design of Selective Acetylcholinesterase Inhibitors.

Acetylcholinesterase is a prime target for therapeutic intervention in Alzheimer's disease. Acetylcholinesterase inhibitors (AChEIs) are used to improve cognitive abilities, playing therefore an important role in disease management. Drug repurposing screening has been performed on a corporate chemical library containing 11 353 compounds using a target fishing approach comprising three-dimensional (3D) shape similarity and pharmacophore modeling against an approved drug database, Drugbank. This initial screening identified 108 hits. Among them, eight molecules showed structural similarity to the known AChEI drug, pyridostigmine. Further structure-based screening using a pharmacophore-guided rescoring method identifies one more potential hit. Experimental evaluations of the identified hits sieve out a highly selective AChEI scaffold. Further lead optimization using a substructure search approach identifies 24 new potential hits. Three of the 24 compounds (compounds 10b, 10h, and 10i) based on a 6-(2-(pyrrolidin-1-yl)pyrimidin-4-yl)-thiazolo[3,2-a]pyrimidine scaffold showed highly promising AChE inhibition ability with IC50 values of 13.10 ± 0.53, 16.02 ± 0.46, and 6.22 ± 0.54 µM, respectively. Moreover, these compounds are highly selective toward AChE. Compound 10i shows AChE inhibitory activity similar to a known Food and Drug Administration (FDA)-approved drug, galantamine, but with even better selectivity. Interaction analysis reveals that hydrophobic and hydrogen-bonding interactions are the primary driving forces responsible for the observed high affinity of the compound with AChE.

Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions.

We here disclosed a new protocol for the condensation of acetophenone derivatives and active methylene compounds with aldehydes in the presence of boric acid under microwave conditions. Implementation of the reaction is simple, healthy and environmentally friendly owing to the use of a non-toxic catalyst coupled to a solvent-free procedure. A large variety of known or novel compounds have thus been prepared, including with substrates bearing acid or base-sensitive functional groups.