As part of an ongoing effort to continue expanding the chemical space of potential epi-drugs, in particular DNMTi, in this work, we report the experimental testing of 12 and 13 and another quinazoline-based derivative (cf. Figure ) with DNMT1, DNMT3A, and DNMT3B in biochemical enzymatic inhibition assays. We also discuss the molecular dynamics (MD) simulations of the most potent compounds to rationalize their enzymatic inhibitory activity at the molecular level. The findings of this work pave the way to continue exploring quinazoline-based derivatives as inhibitors of DNMTs with multi-epigenetic target activity.