DNA-methyltransferases (DNMTs) catalyze the transfer of a methyl moiety from S-adenosyl-L-methionine to the C5 position of cytosine in DNA, a process dysregulated in cancers leading to hypermethylation and silencing of tumor suppressor genes. Developing potent and selective DNMT inhibitors is crucial for cancer therapy. We synthesized 29 analogues of NSC 319745 and evaluated their DNMT inhibitory activity. The effect of selected compounds on methylation level in MDA-MB-231 human breast cancer cells was assessed via a luminometric assay, and molecular docking was used to propose binding modes. Contrary to previous reports, NSC 319745 is not a DNMT inhibitor. All analogues showed less than 20% inhibition against DNMT1 at 100 μM. Seven compounds (24, 26, 28, 29, 49, 50, and 54) significantly inhibited DNMT3A, with compound 49 having an apparent EC50 of 36 μM against DNMT3A. Molecular docking suggested compound 49 binds in the SAM pocket. No activity was detected against EZH2 and DOT1L. A moderate reduction of the methylation level in MDA-MB-231 cells was observed for compound 54 at 200 μM. Compounds 49 and 54 represent potential new starting points for lead optimization programs.