Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase – Design, synthesis and biological evaluation

The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic glutamatergic neurotransmissions small molecules has been suggested as one potential disease-modifying approaches for Alzheimer’s (AD). Tacrine, a potent inhibitor acetylcholinesterase (AChE) is first FDA approved drug treatment AD. Tacrine also low affinity antagonist N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to hepatotoxicity. With an aim develop novel high directed ligands (MTDLs) against AChE NMDAR, reduced hepatotoxicity, we performed silico structure-based modifications on tacrine, chemical synthesis derivatives vitro validation their activities. Nineteen such showed inhibition IC50 values range 18.53 ± 2.09 – 184.09 19.23 nM 0.27 0.05 38.84 9.64 ?M NMDAR. Some selected compounds protected rat primary cortical neurons glutamate induced excitotoxicity. Two derived MTDLs, 201 208 exhibited vivo efficacy rats by protecting behavioral impairment administration excitotoxic agent, monosodium glutamate. Additionally, several these synthesized promising inhibitory activitiy butyrylcholinesterase. MTDL-201 devoid hepatotoxicity vivo. Given therapeutic MTDLs therapy, our studies revealed among which appears be candidate immediate preclinical evaluations.