Design, Synthesis and Biological Evaluation of New Agents for the Treatments of Chronic Degenerative Diseases

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, and the one with the strongest societal impact for what concerns incidence, prevalence, and cost of care. Against this backdrop, the governments and industries have increased their support for drug discovery and development. Glycogen synthase kinase-3β (GSK-3β), is serine/threonine kinase largely expressed in the central nervous system (CNS), it is implicated in the formation of Aβ plaques and neurofibrillary tangles (NFTs), modulates inflammatory response, axonal transport and microtubule dynamics impairment. This thesis deals with the design and synthesis of new non-ATP competitive GSK-3β inhibitors; the present study allowed identifying a new GSK-3β inhibitor in micromolar range, the study of the mechanisms of action for this synthesized compound revealed that it behaves as non-ATP competitive GSK-3β inhibitor; it was evaluated in vivo using zebrafish model. This new hit compound was subjected to a structure-activity relationships campaign and further optimization in order to increase its inhibitory potency and the lipophilicity for better pharmacokinetic properties. This thesis also describes development of agents as MTDLs for AD, new GSK-3 β- HDAC inhibitors were synthesized and tested both in enzyme assays and in SHSY-5Y cells. And a second generation of rhein−huprine hybrids were designed and synthesized with different basicity as MTDLs for AD, the new hybrids endowed with a very interesting multipotent pharmacological profile, as they should be able to block the neurodegenerative cascade associated to AD at different levels. In cancer therapy, DNA topoisomerase inhibitors are amongst the most widely used and effective anticancer drugs target either type I or II enzymes. In this thesis description for the development of 7- and 9-substitued Tryptanthrin derivatives, with the aim of increasing the affinity towards topoisomerases and the cytotoxic activity. As a result, 12 novel derivates were synthesized; biological evaluation is still ongoing towards topoisomerases.