Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents.

INTRODUCTION

The multi-targeted ligands (MTDL) strategy has been recognized as a promising Approach for the development of effective treatments against Alzheimer's disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were designed and synthesized as multifunctional drugs for the treatment of AD.

METHODS

The derivatives were synthesized by chemical methods and their structure was confirmed by nuclear magnetic resonance (NMR). The Ellman's assay was utilized to assess the inhibitory potential of derivatives against AChE and BuChE. The inhibitory activity of these derivatives on both MAO-A and MAO-B was assessed using a fluorescence-based method. The thioflavin T (Th-T) fluorescence assay was used to assess the inhibition of A self-aggregation. The cytotoxicity was evaluated using the MTT assay. The Surflex-Dock program in Sybyl-X2.0 Software was employed for molecular docking.

RESULTS

studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against AChE, and MAO-B (IC < 1 μM), as well as A aggregation (IC < 20 μM). Importantly, the multitarget compounds , , and exhibited remarkable efficacy in simultaneously mitigating A-induced toxicity in SH-SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that , , and possessed favorable pharmacokinetic properties and demonstrated low toxicity levels. Additionally, molecular docking studies of 6d within the activesites of AChE, MAO-B, and A elucidated the inhibition mechanism.

DISCUSSION AND CONCLUSION

Based on these findings, it is evident that , , and hold potential as promising multi-functional drugs for AD treatment.