•22 3-Hydroxypyridin-4-one-resveratrol hybrids were designed.•3i and 4f are good antioxidants, metal-chelating agents and Aβ anti aggregation.•SAR between compounds and the Aβ1–42 inhibition activity was outlined.A series of deferiprone-resveratrol hybrids have been designed and synthesized as multitarget-directed ligands (MTDLs) through merging the chelating moiety 3-hydroxypyridin-4-one into the structure of resveratrol, a natural antioxidant agent and β-amyloid peptide (Aβ) aggregation inhibitor. The in vitro biological evaluation revealed that most of these newly synthesized compounds exhibited good inhibitory activity against self-induced Aβ1–42 aggregation, excellent antioxidant activity and potent metal chelating capability. Compounds 3i and 4f were identified as the most promising MTDLs with triple functions, possessing micromolar IC50 values for Aβ1–42 aggregation inhibition, greater 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS•+) scavenging activity than Trolox and similar pFe(III) values to that of deferiprone.Download high-res image (163KB)Download full-size image

•Introduction of metal-chelating functional groups on fluoropyridine.•Selective lithiation on fluoropyridine.•Carboxylation to introduce an amido functional group.Starting from fluoropyridines as a building block, with chelating functional groups being introduced, several fluoro- and amido-disubstituted 3-hydroxypyridin-4-ones have been synthesized with the intention of improving the pharmaceutical profile of 3-hydroxypyridin-4-ones.Starting from fluoropyridines as a building block, with chelating functional groups being introduced, several fluoro- and amido-disubstituted 3-hydroxypyridin-4-ones have been synthesized.