A series of new hybrid compounds was prepared combining tetrahydropyran rings with different aromatic systems by means of a 1,2,3‐triazole, using a building block strategy. The design of these structures was guided by Lead‐Likeness and Molecular Analysis (LLAMA) software, adding modifications to our most potent scaffold (the tetrahydropyran ring) to generate promising “lead‐like” candidates, which were subsequently compared against reported anticancer compounds. Our synthesized compounds demonstrated significant antiproliferative activity when compared with the standards cisplatin and 5‐fluorouracil, across a panel of six different tumor cell lines. Moreover, compared with our group's previous hybrid compounds, these new structures exhibit similar activity while offering simpler synthesis and greater potential for structural diversification, a fact that was previously an issue. Further investigations on the most active compounds included assessments of reproductive cell survival, inhibition of cell migration, and effects on nuclear morphology, indicating potential diverse mechanisms of action for these compounds. Pharmacokinetic properties were also calculated for the whole series of compounds using the pkCSM online software.