The βhematin formation is a unique process adopted by sp. to detoxify free heme and represents a validated target to design new effective antimalarials. Most of the βhematin inhibitors are mainly based on 4-aminoquinolines, but the parasite has developed diverse defense mechanisms against this type of chemical system. Thus, the identification of other molecular chemical entities targeting the β-hematin formation pathway is highly needed to evade resistance mechanisms associated with 4-aminoquinolines. Herein, we showed that the highly coordinative character can be a useful tool for the rational design of antimalarial agents targeting β-hematin crystallization. From a small library consisting of five compound families with recognized antitrypanosomatid activity and coordinative abilities, a group of tetradentate 1,4-disubstituted phthalazin-aryl/heteroarylhydrazinyl derivatives were identified as potential antimalarials. They showed a remarkable curative response against -infected mice with a significant reduction of the parasitemia, which was well correlated with their good inhibitory activities on β-hematin crystallization (IC = 5-7 μM) Their inhibitory and responses were comparable to those found for a chloroquine reference The active compounds showed moderate toxicity against peritoneal macrophages, a low hemolysis response, and a good ADME profile, identifying compound as a promising antimalarial agent for further experiments. Other less coordinative fused heterocycles exhibited moderate inhibitory responses toward β-hematin crystallization and modest efficacy against the model. The complexation ability of the ligands with iron(III) was experimentally and theoretically determined, finding, in general, a good correlation between the complexation ability of the ligand and the inhibitory activity toward β-hematin crystallization. These findings open new perspectives toward the rational design of antimalarial β-hematin inhibitors based on the coordinative character as an alternative to the conventional β-hematin inhibitors.