Development of quinazolinone and vanillin acrylamide hybrids as multi-target directed ligands against Alzheimer’s disease and mechanistic insights into their binding with acetylcholinesterase

Abstract

In view of Multi-Target Directed Ligand (MTDL) approach in treating Alzheimer’s Disease (AD), a series of novel quinazolinone and vanillin cyanoacetamide based acrylamide derivatives (9a-z) were designed, synthesized, and assessed for their activity against a panel of selected AD targets including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), amyloid β protein (Aβ), and also 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and neuroprotective activities. Five of the target analogs 9e, 9h, 9 l, 9t and 9z showed elevated AChE inhibitory activity with IC50 values of 1.058 ± 0.06, 1.362 ± 0.09, 1.434 ± 0.10, 1.015 ± 0.10, 1.035 ± 0.02 µM respectively, high inhibition selectivity against AChE over BChE and good DPPH radical scavenging activity. Enzyme kinetic studies of the potent hybrids in the series disclosed their mixed inhibition approach. Active analogs were found to be non-toxic on SK-N-SH cell lines and have excellent neuroprotective effects against H2O2-induced cell death. Strong modulating affinities on Aβ aggregation process were observed for most active compounds since; they irretrievably interrupted the morphology of Aβ42 fibrils, increased the aggregates and declined the Aβ-induced toxicity in neurons. From the fluorescence emission studies, the binding constants (K) were determined as 2.5 ± 0.021x103, 2.7 ± 0.015x103, 3.7 ± 0.020x103, 2.4 ± 0.013x104, and 5.0 ± 0.033x103 M−1 and binding free energies as −5.82 ± 0.033, −6.07 ± 0.042, −6.26 ± 0.015, −7.71 ± 0.024, and −6.29 ± 0.026 kcal M−1 for complexes of AChE–9e, 9h, 9 l, 9t and 9z, respectively. Moreover, the CD analysis inferred the limited modifications in the AChE secondary structure when it binds to 9e, 9h, 9 l, 9t and 9z. On the basis of docking studies against AChE, the most active congeners were well oriented in the enzyme’s active site by interacting with both catalytic active site (CAS) and peripheral anionic site (PAS). In summary, these quinazolinone and vanillin acrylamide hybrid analogs can be used as promising molecular template to further explore their in vivo efficiency in the development of lead compound to treat AD. Communicated by Ramaswamy H. Sarma