Design, synthesis, and biological evaluation of novel N'-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer's disease

Alzheimer's Disease (AD) is one of the most devastating chronic health problems of the last few decades. Unfortunately, current treatment and care options for AD are insufficient, making it a prominent topic for drug discovery studies. Currently, AD drug development studies have focused on the strategy of multitarget directed ligands (MTDLs). Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, we designed and synthesized novel eight N'-(4-oxo-4H-chromen-3-yl)methylene propanehydrazide derivatives. We then evaluated the inhibition potency of all final compounds for cholinesterase enzymes. Among them, (6f) (IC50 AChE=16.91 mu M) was found to be the most potent acetylcholinesterase inhibitor. Additionally, (6d) (IC50's AChE=26.91 mu M and BChE=47.94 mu M) exhibited dual cholinesterase inhibitor activity. Moreover, we investigated all title compounds for their antioxidant (DPPH, ORAC) and metal chelator activities. According to the ORAC-FL results, all the compounds exhibited good antioxidant activity ranging from 4.082 to 16.715 Trolox equivalents. We also observed chelator effects of all compounds for Cu(II), Fe(II), and Zn(II) ions at varying rates. Furthermore, we assessed the in-silico physicochemical parameters of the compounds to evaluate their drug-likeness or druggability.