Antimalarial Activity of Highly Coordinative Fused Heterocycles Targeting β-Hematin Crystallization

Abstract

The β-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 β-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 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 Plasmodium berghei-infected mice with a significant reduction of the parasitemia, which was well correlated with their good inhibitory activities on β-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 β-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 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.

High CT-Fluorophore Featuring a Basic Moiety into D–A Chain as a pKa Probe

“…From a perspective, we think that the use of a high CT probe bearing a basic moiety in the D–A chain may also be a convenient platform for the recognition of other chemical events dependent on the acidity, such as (i) the acidity of metals (hard–soft acid–base properties), (ii) identification of halogen-bonded adducts, and (iii) recognition of a hydrogen-transfer process upon excitation, such as PCET mechanisms through selective disruption of the ICT mechanism. Furthermore, the biological potential of N 1 -aryl-2-(trifluoromethyl)­benzo­[ b ]­[1,8]­naphthyridin-4­(1 H )-ones as antiparasite agents , opens the door to explore the location and distribution of the probe through fluorescence microscopy using the quenching fluorescence derived from the interaction with acid species into the target cell.…”

Synthesis and Antitrypanosomal and Mechanistic Studies of a Series of 2-Arylquinazolin-4-hydrazines: A Hydrazine Moiety as a Selective, Safe, and Specific Pharmacophore to Design Antitrypanosomal Agents Targeting NO Release

“…The geometry of all tested compounds were optimized, and HOMO–LUMO orbital frontiers and EPS were obtained. Theoretical calculations were performed according to the reported strategy for similar structures . HOMO and LUMO frontier orbital maps for compounds and data are shown in Figures S6–S9 and Table S2.…”

“…Theoretical calculations were performed according to the reported strategy for similar structures. 54 HOMO and LUMO frontier orbital maps for compounds and data are shown in Figures S6–S9 and Table S2 .…”

“…Theoretical calculations were performed according to the reported strategy for similar structures. 54…”

A photobasic D–A fluorophore with a high intramolecular charge-transfer as a model strategy for designing organic proton-coupled electron-transfer modulators: an analysis based on steady-state fluorescence, isotopic effect and theoretical study

“…Specific disruption of this photophysical mechanism can derive specific fluorescent responses that are of great applicability for the design of organic light-emitting diodes, solar energy conversion, nonlinear optical materials and fluorescent sensors. 44 Recently, we demonstrated that inserting a high-CT fluorophore featuring an internal basic moiety into a D–A chain like the N 1 -aryl-2-(trifluoromethyl)benzo[ b ][1,8]naphthyridin-4(1 H )-one 3k 45 acts as a convenient p K a probe, which shows a selective quenching response as a function of the acidity of the tested acid. 46 The chemical system was also characterized as having a remarkable dominant charge-transfer (CT) state with a relatively high stability (14.10 ns) ( 3k in Scheme 1C).…”