ABSTRACT
The ß-hematin formation is a unique process adopted by Plasmodium sp. to detoxify free heme and represents a validated target to design new effective antimalarials. Most of the ß-hematin 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 ß-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 ß-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 Plasmodium berghei-infected mice with a significant reduction of the parasitemia, which was well correlated with their good inhibitory activities on ß-hematin crystallization (IC50 = 5-7 µM). Their in vitro inhibitory and in vivo responses were comparable to those found for a chloroquine reference. The active compounds showed moderate in vitro toxicity against peritoneal macrophages, a low hemolysis response, and a good in silico ADME profile, identifying compound 2f as a promising antimalarial agent for further experiments. Other less coordinative fused heterocycles exhibited moderate inhibitory responses toward ß-hematin crystallization and modest efficacy against the in vivo 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 ß-hematin crystallization. These findings open new perspectives toward the rational design of antimalarial ß-hematin inhibitors based on the coordinative character as an alternative to the conventional ß-hematin inhibitors.
ABSTRACT
Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I and II clinical trials, respectively. Nevertheless, pharmacodynamic studies have demonstrated that isoquine is highly sensitive to form O-glucuronide metabolite, which may affect its accumulation in tissues. To avoid the O-glucuronide formation and its negative influence in the accumulation process, a series of novel five dehydroxy isoquine derivatives were designed and prepared herein as potential antimalarial agents. By a simple three-step procedure, five dehydroxy isoquines were prepared and subsequently examined on the inhibition of haemozoin formation, the main target of the 4-aminoquinolines. Four derivatives displayed significant inhibitory activities at low IC50 values from 1.66 to 1.86 µM comparable to CQ. On the basis of the results, these four compounds were subsequently tested against Plasmodium berghei ANKA model in mice, showing to be as active as CQ with significant curative responses and parasitemia suppression in mice infected. On the other hand, these four compounds showed an acceptable non specific cytotoxicity on murine peritoneal macrophague and human erythrocyte cells. Thus, the presented data indicate that the dehydroxy isoquines 4b, 4c and 4e constitute promising cost-effective leads for the development of new antiplasmodial targeted at blood-stage malaria parasites.
