ABSTRACT
In this study, we report the synthesis of twenty new acridine-thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC50 = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 104 M-1; Ksv = 2.6 × 103 M-1). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC50 between 11.45 and 17.32 µM.
ABSTRACT
It was evaluated the in vitro efficacy of ethanolic extract of leaves and bark of Ximenia americana L and Schinopsis brasiliensis Engl. alone and in association with erythromycin as modulators of microbial resistance against six clinical isolates of Staphylococcus aureus resistant to erythromycin (SA1-SA6) and S. aureus ATCC 25923 by the microdilution method. The extracts were also subjected to bioassay with Artemia salina. The ethanolic extract of barks of X. americana showed a synergistic effect with erythromycin against SA01, SA03 and SA04. The leaf extract of S. brasiliensis exerted synergistic effect against SA03 and the bark extract showed against SA01 and S03. The results suggest that extracts from S.brasiliensis and X. americana have potential as modulator agents of bacterial resistance, which could be used as adjuvants in the treatment of infections by S. aureus resistant to erythromycin, with previous studies of toxicity.
Se evaluó la eficacia in vitro de los extractos etanólicos de hojas y corteza de Ximenia americana L y Schinopsis brasiliensis Engl solos y en asociación con eritromicina como moduladores de la resistencia microbiana frente a seis aislados clínicos de Staphylococcus aureus resistentes a Eritromicina (SA1-SA6) y S. aureus ATCC 25923, por el método de microdilución. Además se determinó la actividad tóxica de los extractos contra Artemia salina. Solo el extracto etanólico de la corteza de X. americana mostró un efecto sinérgico con la eritromicina frente a SA01, SA03 y SA04. El extracto de las hojas de S. brasiliensis ejerció efecto sinérgico contra SA03 y el extracto de corteza, contra SA01 y S03. Los resultados sugieren que S. brasiliensis y X. americana tienen potencial como agentes moduladores de la resistencia bacteriana, que podrían ser utilizados como adyuvantes en el tratamiento de infecciones por S. aureus resistentes a eritromicina, con estudios previos de toxicidad.
