Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca²⁺ Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties

Abstract

This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities.

Keywords

• calcium channel inhibitors
• proteases inhibitors
• antioxidant response element
• ORAC
• Alzheimer’s disease