Bartolic_2025_Biomolecules_15_

In this paper, we aimed to evaluate whether simple, low molecular mass benzoquinone derivatives, featuring different substituents in para- and meta-position relative to the tert-butyl group, possess biological activities against major targets associated with Alzheimer's disease. The 1,4-benzoquinone derivatives studied herein inhibited both cholinesterases in the micromolar concentration range, generally showing a preference for butyrylcholinesterase over acetylcholinesterase; formed complexes with biometal ions Fe(2+), Cu(2+) and Zn(2+); and displayed a certain BACE1 inhibition. Moreover, the tested compounds displayed certain antioxidant activity via either electron transfer or hydrogen atom transfer mechanisms. The antioxidant capacity of the unsubstituted tert-butyl-1,4-benzoquinone (compound 1) was three times lower than that of the standard antioxidant BHT, while 2,6-disubstituted derivatives (compounds 15 and 7) exhibited peroxyl radical scavenging activity comparable to that of Trolox. Taken together with in silico-predicted low toxicity, good intestinal absorption and favorable oral bioavailability, the presented 1,4-benzoquinone derivatives are promising scaffolds for the design of more complex molecules with enhanced cholinesterase and BACE1 inhibitory activity. Furthermore, they could serve as functional substituents in other structural scaffolds to combine and enhance their biological activities.