Revealing the Binding Process of New 3-Alkylpyridine Marine Alkaloid Analogue Antimalarials and the Heme Group: An Experimental and Theoretical Investigation

Abstract

Synthetic 3-alkylpyridine marine alkaloid (3-APA) analogues have shown good antimalarial activity against Plasmodium falciparum. However, despite their structural originality, their molecular target was unknown. Herein, we report a proposal for the antimalarial mechanism of action of 3-APA analogues through interference with the process of hemozoin (Hz) formation. The interaction between 3-APA analogues and heme groups was investigated employing an in silico approach and biophysical techniques such as ultraviolet-visible light (UV-vis) titration and electrospray ionization-mass spectrometry (ESI-MS). The in silico approach was performed based on pure ab initio electronic structure methods in order to obtain insights at the molecular level concerning the binding process of antimalarial drugs at their target site, the heme group. In silico results showed that the formation of heme:3-APA complexes at a molecular ratio of 2:1 are more stable than 1:1 complexes. These results were further confirmed by experimental techniques, such as UV-vis and high-resolution mass spectrometry (ESI-TOF), for two of the most active 3-APA analogues.

Target-Guided Synthesis and Antiplasmodial Evaluation of a New Fluorinated 3-Alkylpyridine Marine Alkaloid Analog

“…Hard acid/base interactions are predominantly electrostatic. This qualitative principle is in line with our theoretical findings because in our previous work, 9 we have shown that the driving force responsible for 2:1 complex formation is electronic energy (Δ E ). In addition, it is important to highlight that the bonding between hard acids and bases can be properly described by the quantum mechanical calculations applied here.…”

“…Furthermore, the energetic results found here are similar to those reported for azide analogs (N 3 – ), from the first generation of 3-APA analogs, which have shown small IC 50 values and favorable binding energies. 9 Azide also presents hard/borderline base characteristics. Hard acid/base interactions are predominantly electrostatic.…”

“…In the present work, we used the same theoretical methodology, that is, UB3LYP with a mixed basis set, as described in our recent paper. 9 The basis set used for all oxygen, fluorine, nitrogen, and iron atoms was 6-31G(d,p). For the atoms belonging to the CH n groups, a minimal STO-3G basis set was assigned.…”

“…These 3-APA analogs target hematin and are able to form stable complexes at a molecular ratio of 2:1 (hematin/3-APA). 9 …”

Halogenation as a Strategy to Improve Antiplasmodial Activity: A Report of New 3-Alkylpyridine Marine Alkaloid Analogs

“…7 Moreover, by adopting in silico simulation and biophysical techniques, our research group proposed that the mechanism for the antimalarial action of these analogs is through interference with the process of hemozoin formation. 8 Some 3-APA analogs with a short alkyl chain, however, were considered inactive against P. falciparum in vitro (in-house library of compounds). As an example, compound 5 exhibited a high IC 50 value (210.7 µM) but was found to interact with hematin in a pattern similar to that of chloroquine (CQ) (Figures 1a and 1b).…”