Design synthesis in silico in vitro and in vivo evaluation of novel l-cysteine derivatives as multi-target-directed ligands for the treatment of neurodegenerative diseases

Abstract

There are four major molecular mechanisms involved in the neuronal cell death are excitotoxicity, neuroinflammation, apoptosis and oxidative stress. Our objective is to explore in silico, in vitro and in vivo evaluation of neuroprotective potential of novel l-Cysteine derivatives as multi-target-directed drugs to manage neurodegenerative diseases. Fifty molecules were designed and included in the in silico analysis to evaluate their druglikeness and binding affinities towards the selected target proteins using various pharmacokinetic and docking software. Based on in silico results and synthetic feasibility, nine compounds were selected for synthesis, spectral analysis, in vitro and in vivo neuroprotective evaluation on neuroblastoma cell line and aluminium induced neurotoxicity in rats. Selected compounds gained best docking score and obey Lipinski’s rule of five. In vitro results showed that the compound 1a and 1b significantly increased the percentage viability (81.03 ± 4.78 and 76.1 ± 1.99) of human neuroblastoma cells at concentration of 100 µg. Mean retention latencies and oxidative stress were significantly decreased (P < 0.01) in test 2 and test 3 groups on day 21 and 42 when compared to disease control. In vitro study revealed the significant neuroprotective effect of compound 1a and 1b against glutamate induced neurotoxicity in SH SY-5Y cell line. The retention latency and biochemical parameters suggest that 1a has neuroprotective effect in aluminium induced Alzheimer’s disease model in rats.