Discovery of multi-target directed 3-OH pyrrolidine derivatives through a semisynthetic approach from alkaloid vasicine for the treatment of Alzheimer's disease

Vasicine is a pyrroloquinazoline alkaloid, which has been isolated from the plant Adhatoda vasica. Naturally inspired semi-synthetic transformations were prepared using vasicine as a synthetic precursor to overcome Alzheimer's disease (AD). These semi-synthetic analogs exhibited stable interactions and were well resided at AChE and BChE active sites in in-silico studies. Further, in-vitro experiments were performed to assess the cholinesterase inhibitory activity and reduction of amyloid-beta (Aβ_1-42) plaques potency, PAMPA assay permeability, and antioxidant activity, these findings suggested that compound VA10 can be a lead molecule among all the synthesized analogs. The compound VA10 binds towards AChE peripheral anionic site (PAS) property was established through propidium iodide displacement assay. Moreover, VA10 showed no notable cytotoxicity and exhibited neuroprotective nature on Aβ_1-42 treated SH-SY5Y cell line. In addition, VA10 was found to be safe in rats, which was confirmed by acute oral toxicity studies. Furthermore, in-vivo studies suggested that compound VA10 (10 mg/kg, p.o) ameliorated the memory and cognition impairment in scopolamine-induced amnesia model and Aβ_1-42 induced Alzheimer rat model. Ex-vivo studies of compound VA10 demonstrate improved ACh levels by inhibiting AChE activity in rat brain. Moreover, histopathological observations on rats brain sections indicate VA10 (10 mg/kg, p.o) recovered the neuronal cells at hippocampus region (DG, CA3, and CA1). These positive experimental data from in-silico, in-vitro and in-vivo studies, suggested that compound VA10 can be a lead compound for further preclinical development studies as a naturally derived alkaloid for anti-AD.

Acetylcholine; Alzheimer's disease; Amyloid-beta; Memory impairment; Pyrroloquinazoline alkaloids; Vasicine.