Alzheimer's diseases(AD) has been discovered and under research for more than 70 years, However there is no cure for these progressive and devastating diseases. Based on the following hypothsis: Aß metabolite problem/over production result in the accumulation, and lead to aggregation is the cause of Alzheimer’s disease. AApeptide and Melatonin derivatives can bind to Aß and block the aggregation of β amyloid monomers, decrease the toxicity of Aß to neurons and slow the progressive of Alzheimer’s diseases. In addition, AApeptide which mimic transmembrane peptide Tat will have similar transmembrane function. We have set up our goals as follows: 1) Using newly discovered peptidomimetics, AApeptides. We moved on to research to discover their potential of transmembrane activity and anti-Alzheimer's acitiviy. 2) In Addition, studies of small molecule melatonin derivatives were also progressed. Methods include in this research includes bioorganic synthesis, identification of spectroscopy and relative assays targeting on biological efficiency of Anti-Alzheimer’s diseases. The details of which will be described in Chapters. In conclusions, two sets of transmembrane peptidomimetics for drug transportation has been successfully evaluated and potential of AA peptide small molecules, melatonin derivativesare also evaluated. These works have gained good progress in research between AApeptide and Alzheimer’s Diseases. These works also established basis of research in developing peptidomimimetics as potential pharmacies against Alzheimer’s diseases.

Melatonin (N-acetyl-5-methoxytryptamin, MLT) is a naturally occurring antioxidant which has shown some potential for use as a spin trap. Spin traps react with short lived hydroxyl radicals (HO·) to produce more stable products called spin adducts which may be characterized by electron paramagnetic resonance spectroscopy. However, the relative stability of hydroxyl spin adducts of melatonin derivatives (MLTD) compared to 2-hydroxymelatonin (HO-MLT) has not been examined computationally. Computational studies have been done on four selected MLTD; methylmelatonin (Me-MLT), chloromelatonin (Cl-MLT), cyanomelatonin (CN-MLT), and nitromelatonin (NO2-MLT). Geometry of the structures were optimized at the HF/6-31G(d), cc-pVXZ, (X=D and T) and DFT/B3LYP/6-31G(d), cc-pVDZ and cc-pVTZ levels of theory and extrapolated to the complete basis set limit using cc-pVXZ (X=D, T) basis sets. The lowest relative energy was found to be a mix of results for 2-OH-MLT-Me at HF and 2-OH-MLT-NO2 at DFT.