The objective of this research is to generate leads for developing our ultimate\npoly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active\nmolecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling\n(via cholinesterase inhibition) are still being sought for combating Alzheimerââ?¬â?¢s disease (AD).\nWe differentiate ââ?¬Å?poly-activeââ?¬Â agents from ââ?¬Å?multi-targetââ?¬Â ones by defining them as single\nmolecular entities designed to target only specific contributory synergistic pharmacologies in\na disease. For instance, in AD, free radicals either initiate or act in synergy with other\npharmacologies, leading to disease worsening. For this preliminary report, a total of 14\n(i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives\nwere synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and\ninhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives\n(4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance\ncapacity (ORAC) assay. The antioxidant values were either comparable or more potent than the\ncomparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c)\nyielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base\nsearch confirmed that most of the compounds reported herein are new, except 9a and 9c which are\nalso commercially available.
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