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Background: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound-namely RDS 344-as a potential innovative anticancer agent., Methods: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells., Results: The most interesting compound was the N -benzyl counterpart of RDS 3442, namely 2a , that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC 50 s ranging from 4 and 8 μM, 4-13 times more active of hit., Conclusions: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype.