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Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are neurodegenerative disorders which affect mammals, including the human species, and arise after the conversion of the monomeric cellular prion protein (PrP
C
) into the aggregated scrapie form (PrP
Sc
). There is no therapy to treat TSEs and the identification of compounds that bind PrP
C
, preventing its conversion into PrP
Sc
, is a viable therapeutic strategy. We designed and synthesized six novel trimethoxy-benzamide compounds as anti-prion drug candidates. Molecular docking analyses predicted that all the derivatives bind to a
hotspot
region located in the PrP globular domain with very similar spatial orientation and interaction mode. Although none of the analogs inhibited in vitro-aggregation of recombinant PrP (rPrP) in a cell-free conversion assay, the RT-QuIC, compound
8a
accelerated rPrP conversion into PrP
Sc
-like species. STD-NMR and ITC analyses indicated that both
8a
and
8b
bind to rPrP
90–231
. These analogs were toxic to PrP
Sc
-infected cell lines, hence we could not assess their anti-prion activity by using this cellular approach, although this toxicity was cell line-dependent. These results point out that the 4-amino-quinoline trimethoxy-benzamide scaffold described herein represents a novel chemical pattern useful as a starting point for future structural optimization in the design of PrP ligands with improved affinity and safety profiles.