Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease

In this work, based on the potential anti-AD molecule previously studied by our group, we continue to introduce different substituents at different positions to improve both drug-like properties and on target activities. 33 N- salicyloyl tryptamine-carbamate hybrids were designed, synthesized and evaluated as cholinesterase inhibitors. H327 was the most potent BChE inhibitor (eqBChE IC50= 0.057 +/- 0.005 mu M), and showed threefold improved inhibitory potency than the positive drug rivastigmine (eqBChE IC50 = 0.19 +/- 0.001 mu M). In addition, H327 as a pseudo-irreversible BChE inhibitor was endowed with neuroprotective, antioxidative and anti-neuroinflammatory properties. Cytotoxicity and acute toxicity tests confirmed the safety of compound H327. The pharmacokinetics study showed that compound H327 had a longer T1/2 time and higher bioavailability than the lead compound 1 g. Compound H327 was able to cross the blood-brain barrier (BBB) in vivo. Moreover, the behavioral tests showed that compound H327 could significantly improve scopolamine-induced cognitive impairment in vivo. Overall, these results demonstrated that compound H327 is a promising multi-target agent for the treatment of AD.

Automated summary

Based on a previously studied anti-AD molecule, this work introduces different substituents at different positions to improve drug-like properties and on target activities. A total of 33 N-salicyloyl tryptamine-carbamate hybrids were designed, synthesized, and evaluated as cholinesterase inhibitors. Compound H327 showed the highest potency as a BChE inhibitor and demonstrated neuroprotective, antioxidative, and anti-neuroinflammatory properties. Pharmacokinetics studies revealed that H327 had better pharmacokinetic parameters and higher bioavailability than the lead compound. Behavioral tests showed that H327 significantly improved scopolamine-induced cognitive impairment. Overall, compound H327 is a promising multi-target agent for the treatment of AD.