Anticholinesterase activities of novel isoindolin-1,3-dione-based acetohydrazide derivatives: design, synthesis, biological evaluation, molecular dynamic study.

In pursuit of developing novel cholinesterase (ChE) inhibitors through molecular hybridization theory, a novel series of isoindolin-1,3-dione-based acetohydrazides (compounds 8a-h) was designed, synthesized, and evaluated as possible acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In vitro results revealed IC50 values ranging from 0.11 ± 0.05 to 0.86 ± 0.02 µM against AChE and 5.7 ± 0.2 to 30.2 ± 2.8 µM against BChE. A kinetic study was conducted on the most potent compound, 8a, to ascertain its mode of inhibition, revealing its competitive mode against AChE. Furthermore, the binding interaction modes of the most active compound within the AChE active site was elucidated. Molecular dynamics simulations of compound 8a were performed to assess the stability of the 8a-AChE complex. In silico pharmacokinetic predictions for the most potent compounds indicated their potential as promising lead structure for the development of new anti-Alzheimer's disease (anti-AD) agents.

In silico and In vitro Assessment of Antibacterial Activity, LPS Binding Affinity, and Toxicity of the GKY25 Peptide.

INTRODUCTION: Extensively and multi-drug resistant isolates of bacteria (MDR, XDR) have caused significant health problems and are responsible for high morbidity and mortality as well. In this critical condition, the discovery, design, or development of new antibiotics is of great concern. According to this necessity, antimicrobial peptides (AMPs) suggested as promising agents. Accordingly, this study aims to evaluate the GKY25 peptide to develop its future antibacterial applications as well as confirmation of LPS neutralization. METHODS: Predictions of 3D structure and helical wheel projection analysis of the peptide were performed by ITASSER and Heliquest servers. Binding affinity and antibacterial activity were performed using molecular docking and CAMPR4, respectively, followed by experimental binding assay as well as in vitro antibacterial assay. RESULTS: GKY25 was predicted as an alpha-helical peptide, and its helicity showed probable projection of hydrophobic and positively-charged amino acid residues. Docking studies showed binding affinity of GKY25 peptide to gram-positive and outer and inner gram-negative bacterial membranes as -5.7, -6.8, and -4 kcal/mole, respectively. CAMPR4 analysis predicted the peptide as an AMP. Experimental binding assay showed that the peptide binds LPS immediately and their interaction was observed at 274 nm. CONCLUSION: Gathering all in silico and in vitro data together, GKY25 is a good drug lead that could be examined further using clinical isolates of gram-negative bacteria in vitro.