Discovery of novel series of 2-substituted benzo[d]oxazol-5-amine derivatives as multi-target directed ligands for the treatment of Alzheimer's disease.

Discovery of novel series of 2-substituted benzo[d]oxazol-5-amine derivatives as multi-target directed ligands for the treatment of Alzheimer's disease. Eur J Med Chem. 2019 Aug 14;182:111613 Authors: Gutti G, Kakarla R, Kumar D, Beohar M, Ganeshpurkar A, Kumar A, Krishnamurthy S, Singh SK Abstract Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzo[d]oxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052 ± 0.010 μM), BuChE (IC50 = 1.085 ± 0.035 μM), and significant amyloid-beta aggregation (20 μM) inhibition. The compound possessed better blood-brain barrier permeability (Pe = 10.80 ± 0.055 × 10-6 cm s-1) in PAMPA assay and neuro protective properties (40 μM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research