Multipharmacophore strategy in medicinal chemistry for the design of drugs for the treatment of Alzheimer's and some other neurodegenerative diseases

A strategy for the design of potential drugs for the treatment of neurodegenerative diseases is considered. This strategy is based on multipharmacophore compounds combining several characteristic structural moieties (scaffolds) of different neuroactive substances within the one molecule. Various synthetic approaches to such compounds are considered and exemplified by the synthesis of conjugates of phenothiazine, tetrahydro-gamma-carboline, carbazole, and aminoadamantane moieties linked through a series of spacers. Data on the biological activity of compounds acquired within the framework of complex screening system are presented. In particular, effects of the novel compounds on cholinesterase enzyme systems, glutamate receptors, mitochondrial structures, formation of microtubule systems, as well as their antioxidant properties, were evaluated. For some multipharmacophore structures, the appearance of neurobiological properties that are not characteristic of the parent compounds was observed, thus providing new opportunities for the design of original highly efficient multitarget drugs. The acquired results allowed us to select several leading compounds that have successfully passed preclinical trials.