MULTITARGET-DIRECTED SYNTHESIS OF NOVEL DRUG INHIBITORS: IN VITRO AND IN SILICO STUDIES FOR ALZHEIMER’S DISEASE

Abstract

The aggregation of Amyloid-β, hyper-phosphorylation of tau, are fundamental processes involved in Alzheimer's progression and the mis-regulation of kinases such as DYRK1A and CLK1 play importance in disease progression. This study is a series of novel dual CLK1/DYRK1A inhibitors that were rationally designed, synthesized and tested using an integrated medicinal chemistry (IMC) approach. The compounds were synthesized by a multi-step procedure that involves the formation of key intermediates, in addition to CF being used as catalyst in the procedure, with high purity and very well preserved structural integrity and confirmed using FT-IR, ¹H NMR, ¹³C NMR, DEPT-135, HRMS, LC–MS and HPLC. The results from molecular docking showed high binding ability of the compounds in the ATP binding pocket with both DYRK1A and CLK1 with good hydrogen bonding & hydrophobic interaction. In addition, MM GBSA calculation revealed the stability of the protein–ligand complexes, and good drug-likeness, as well as permeability to BBB, was displayed based on their MD simulation. ATP competitive inhibition was seen in in vitro assays with DYRK1A and CLK1 along with known neuroprotective effects in cell models of SH-SY5Y and HEK293-Tau, with a dramatic decrease in the levels of tau phosphorylation. Overall, the results shown here indicate that these compounds can be used as lead compounds in developing mutitarget directed therapeutics for the key kinases involved in the Alzheimer's disease pathology