Alzheimer’s disease is the most common cause of dementia, and its associated cost represents a staggering weight for world economies. Its current treatment is merely symptomatic, thus making the search for new drugs capable of altering the course of the disease of great interest. Drugs currently in therapeutics for other neurodegenerative diseases such as riluzole share a common scaffold of 2- aminobenzothiazole that confers them interesting neuroprotective properties through ROS scavenging or NMDA antagonism.
The synthesis and chemical characterization of a family of 51 compounds bearing this scaffold was carried out using the Schotten-Baumann reaction, one-pot and two-step amide formation methodologies.1 The new compounds were assessed in a phenotypic model of differentiated neuron- like SH-SY5Y cells transfected with MAPT P301L and APP V717I mutations to test their protective activity against b-amyloid and hyperphosphorylated tau aggregation-induced damage by high- throughput screening.2 The neuroprotective effects of these compounds were studied in the model by measuring intracellular calcium levels after excitation and neurite length. Furthermore, a high- throughput kinetic solubility assay was carried out to aid with future molecule modifications.
Two compounds out of the 51 assayed were able to exert a remarkable dose-dependent neuroprotective effect against the induced damage. The lipophilicity of the compounds modulated by the substitution patterns3 of the scaffold seems to play a key role in their activity as demonstrated by the comparison of the results in the solubility assay and in the phenotypic model.
