Antitrypanosomal activities and cytotoxicity of some novel imidosubstituted 1,4-naphthoquinone derivatives

Abstract

The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC50 = 10.67 µM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 µM to 6.1 µM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).

Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives

“…Similarly, 2, 3-diphenyl-1, 4-naphthoquinone (DPNQ), was found to be effective against T. cruzi [14]. Previously, some novel imido-1, 4-naphthoquinone derivatives [15], were synthesized and investigated for anti-trypanosomal activities. Some of them showed remarkable anti-trypanosomal activity at G2/M of the cell cycle [15].…”

“…Previously, some novel imido-1, 4-naphthoquinone derivatives [15], were synthesized and investigated for anti-trypanosomal activities. Some of them showed remarkable anti-trypanosomal activity at G2/M of the cell cycle [15]. Since the cell cycle arrest pointed to tubulin disruptive processes, experiments were designed to evaluate activities of five selected imido-1, 4-naphthoquinone ligands against T. cruzi tubulin assembly (Table 1).…”

“…A recent study showed that imido-substituted 1, 4-naphthoquinones are more potent anti-trypanosomal agents than the clinically used Nifurtimox by the arrest of T. cruzi cell proliferation at the G2/M phase [15]. Since the cell cycle arrest pointed to a tubulin disruptive process, we hypothesized that the anti-trypanosomal activities occurred via T. cruzi tubulin polymerization inhibition, an idea that provided the impetus to pursue a novel drug design for Chagas disease via the targeting of T. cruzi tubulin.…”

Genotoxicidad del nifurtimox en deferentes líneas celulares utilizando el ensayo cometa

“…Estas actividades dependieron de la concentración del medicamento y del tipo de célula utilizado. La variabilidad en la toxicidad del nifurtimox ha sido demostrada en ensayos in vitro utilizando varios tipos de células de mamífero hospederas del T. cruzi ya que este medicamento es utilizado como medicamentos de referencia en estudios de screening de nuevos compuesto anti-tripanosomas (26)(27)(28)(29). Igualmente y dado que el nifurtimox está siendo evaluado como medicamento en el tratamiento de algunos canceres como neuro y meduloblastoma, su actividad antitumoral ha sido demostrada en diferentes tipos de células cancerosas (30).…”

Tripanosomiasis americana, una mirada desde el tratamiento

“…En la búsqueda de nuevos agentes antitripanosomiásicos selectivos, con poca o ninguna toxicidad para las cé-lulas de mamíferos, se han desarrollado once análogos del 1,4-naftoquinona imido-sustituida como una nueva clase de agente contra los tripanosomas (40) , y se han buscado nuevos blancos terapéuticos moleculares que no sean compartidos por los hospederos, como lo son las enzimas del sistema antioxidante dependiente de tripanotión (péptido similar al glutatión), presente en los tripanosomátidos y en el T. cruzi; estos nuevos blancos terapéuticos parecen ser la solución para el desarrollo de los nuevos tripanocidas (36) . Además, se han llevado a cabo ensayos ELA (siglas en inglés, enzyme linked aptamer) para buscar en roedores murinos infestados con T. cruzi posibles biomarcadores que sirvan para la monitorización y evaluación de los futuros fármacos antitripanosomiásicos (41) .…”