From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

Abstract

Multitarget directed ligands (MTDLs) are arising as promising tools to tackle complex diseases. The main goal of this work is to create powerful modulating agents for neurodegenerative disorders. To achieve this aim, we have combined fragments that inhibit key protein kinases involved in the main pathomolecular pathways of Alzheimer's disease (AD) such as tau aggregation, neuroinflammation and decreased neurogenesis, whilst looking for a third action in beta‐secretase (BACE1), responsible of β‐amyloid production. We obtained well‐balanced MTDLs with in vitro activity in three different relevant targets and efficacy in two cellular models of AD. Furthermore, computational studies confirmed how these compounds accommodate adequately into the long and rather narrow BACE1 catalytic site. Finally, we employed in situ click chemistry using BACE1 as protein template as a versatile synthetic tool that allowed us to obtain further MTDLs.

Quinazoline-based VEGFR-2 inhibitors as potential anti-angiogenic agents: A contemporary perspective of SAR and molecular docking studies

“…Garofalo et al synthesized several compounds by inserting urea, carbamic acid ester, or amide groups linked to the C-4' position of the anilinoquinazoline scaffold (68). These compounds are multi-target-directed-ligands (MTDLs), a family of compounds described as promissing tools to tackle complex diseases (69). Comparing these groups, amide derivatives did not have the desired inhibitory activity, carbamate counterparts presented a dual EGFR/VEGFR-2 activity, and urea derivatives had the best VEGFR-2 inhibition.…”

“Click Chemistry”: An Emerging Tool for Developing a New Class of Structural Motifs against Various Neurodegenerative Disorders

“…The ability of compound 27 to reduce the toxicity of Aβ40 and Aβ42 was also checked using human neuroblastoma SH-SY5Y cell lines (SK-APP cells). The excellent results prompted researchers to focus on the synthesis of further compounds …”

“…The excellent results prompted researchers to focus on the synthesis of further compounds. 57 The synthesis of 26 (Scheme 10) began with the reaction of 4-(bromomethyl)benzoic acid (a10) to form 4-(bromomethyl)benzoyl chloride (b10). The compound was then converted to benzamide (c10).…”