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Antimalarial Activity of Highly Coordinative Fused Heterocycles Targeting βHematin Crystallization. | LitMetric

Antimalarial Activity of Highly Coordinative Fused Heterocycles Targeting βHematin Crystallization.

ACS Omega

Caítedra de Química General, Facultad de Farmacia, Universidad Central de Venezuela, Los Chaguaramos, Caracas 1041-A, Venezuela.

Published: March 2022

AI Article Synopsis

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908514PMC
http://dx.doi.org/10.1021/acsomega.1c05393DOI Listing

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