A synthetic Benzothiazole-Thiourea Derivative with Multi-Target Potential Activity for Alzheimer's Disease: Antioxidant Properties and Mechanistic Insights.
TL;DR
The antioxidant activity and the potential effects of H74 on multiple targets associated with Alzheimer's disease (AD) were investigated and molecular docking results suggested that H74 might act as a potential inhibitor to these enzymes.
Abstract
H74 is a benzothiazole derivative bearing a thiourea moiety molecule that was synthesized in our laboratory. The antioxidant activity and the potential effects of H74 on multiple targets associated with Alzheimer's disease (AD) were investigated. The anticholinesterase and the antioxidant activities of H74 were tested in vitro. The antioxidant activity of H74 was further evaluated in vivo in aged NMRI mice. The cytotoxicity of H74 was evaluated in Uppsala 87 Malignant Glioma (U87-MG) cells using the MTT assay. Whereas, the drug-likeness and potential multitarget activity of H74 against AD were analyzed using in silico approaches. H74 was potent in inhibiting Acetylcholinesterase (AChE) activity and reducing ABTS and DPPH radicals and scavenging H2O2. H74 inhibited as well lipid peroxidation in rat liver homogenate and the autoxidation of reduced glutathione (GSH) in alkaline medium. The administration of H74 to aged NMRI mice for three days (50 mg/kg/day, i.p.) induced antioxidant effect in the brain reflected by a significant decrease in MDA levels and an increase in GSH levels, although the increase in GSH was not statistically significant. However, H74 showed cytotoxicity by reducing the viability of U87 MG cells. ADME analysis revealed that H74 fits in the drug-likeness rules. SwissTargetPrediction suggested that H74 might interact with several major targets of AD, namely, Cyclin dependent kinase 5, (CDK5), Glycogen synthase kinase 3 beta (GSK3β), beta-Secretase 1(BACE1), AChE. Molecular docking results further suggested that H74 might act as a potential inhibitor to these enzymes. Molecular dynamics (MD) simulations supported the structural stability of the simulated protein-H74 complexes throughout the 200 ns simulation period. Further studies are required to experimentally validate the multitarget effects of H74 on AD-related targets and to evaluate its efficacy in experimental models of AD.