Synthesis,Biological Evaluation,and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC₅₀ values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.     

Proline derived spirobarbiturates as highly effective beta-turn mimetics incorporating polar and functionalizable constraint elements

A practical and efficient synthesis of spirobarbiturates of type III is reported when NH acidity of the imide function of the hydrophilic linker element allowed the introduction of different substituents. Structural characterization, which was based on both X-ray crystallography and spectroscopic investigations, indicated type II beta-turn formation. Introduction of the molecular scaffold into solid phase peptide synthesis gave rise to spirocyclic neuropeptide analogs.     

Heat-accelerated degradation of solid-state andrographolide

The stability of andrographolide, the major active diterpene lactone from Andrographis paniculata (BURM. f.) WALL. ex NEES., was determined to show that, while crystalline andrographolide was highly stable even at 70 degrees C (75% relative humidity) over a period of 3 months, its amorphous phase degraded promptly. Heat-accelerated conditions revealed second-order kinetics of the decomposition with the rate constant at 25 degrees C (k(25 degrees C)) predicted from the Arrhenius plot of 3.8 x 10(-6) x d(-1). The major decomposed product under elevated temperature (70 degrees C, 75% relative humidity) is 14-deoxy-11,12-didehydroandrographolide.