Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10\u2009n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2\u2005nM), strong antioxidant activity (4.29\u2005equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good \u3b2-amyloid (A\u3b2) anti-aggregation properties (65.6\u2009% at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10\u2009n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4\u2009% cell viability at 1000\u2005\u3bcM), affording good neuroprotection against toxic insults such as A\u3b21-40 , A\u3b21-42 , H2 O2 , and oligomycin\u2005A/rotenone on SH-SY5Y cells, at 1\u2005\u3bcM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease