Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to­lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 µM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.

Synthesis and evaluation of the mutagenicity of 3-alkylpyridine marine alkaloid analogues with anticancer potential.

Theonella sp is an important source of biologically-active 3-alkylpyridine alkaloids (3-APAs) that has shown a wide variety of promising biological effects. In the present work, two new 3-APAs analogues were synthesized based on molecular modeling studies to act as potential antimalarial agents. These theoneladin C analogues, containing the thiocyanate group in their chemical structures, were synthesized and evaluated against Plasmodium falciparum (IC50 values ranging from 2.3 to 5.5µM). The structural and energetic analysis demonstrated a high chemical affinity of the two analogues for their target, the heme group. However, despite the good antimalarial activity, the compounds exhibited high cytotoxicity and a lack of selectivity for human cell lines. These findings prompted us to evaluate the cytotoxicity of these compounds against human cancer cell lines. In order to better understand the mechanisms responsible for the toxicity, a variety of genotoxicity assays were performed in vitro. One of the compounds assayed presented an interesting selectivity and high toxicity to the human colon cancer cell line RKO-AS45-1. In addition, the results of the micronucleus assay, comet assay, Ames assay and annexin-V/propidium iodide staining showed that the synthetic alkaloids were able to induce chromosomal mis-segregation and trigger cell death by apoptosis. These results demonstrate that the compounds assessed herein may be promising prototypes of anticancer chemotherapeutic agents.