Synthesis and Sar (Structure–Activity Relationship) Studies of Marine Alkaloid or Peptide Derivatives for Neurodegenerative Disorders

Abstract

Neurodegenerative diseases (AD/PD) are serious problems of the global population where therapeutic interventions to modify the disease pathology are limited. A great variety of bioactive compounds, especially peptides and alkaloids, are found in marine ecosystems, and they display exceptional structural properties and novel pharmacological potential. This paper concentrated on developing and optimizing marine-derived derivatives of alkaloids and peptides, prior to their testing and analysis using structure-activity relationship (SAR). High purity, yield and stability of a library of derivatives were achieved, made through chemical and semi-synthetic methods. The in vitro tests indicated that some of the compounds demonstrated positive neuroprotective properties, i.e., they increased the viability of the neuronal cells, alleviated oxidative stress, and blocked the aggregation of amyloid-B. Of these, the most promising lead compound with excellent multifunctional activity was found to be halogen-substituted derivative MA-03. SAR analysis supported that focused structural changes played a major role in potency, selectivity and bioactivity. The results emphasize the promising nature of marine natural product scaffolds as potentially useful platforms in drug discovery and make the suggestion that MA-03 is a potential candidate to undergo further preclinical development in the lead compounds against neurodegenerative disorders.