The efficacy of 2-nitrovinylfuran derivatives against Leishmania in vitro and in vivo

Despite recent advances in the treatment of some forms of leishmaniasis, the available drugs are still far from ideal due to inefficacy, parasite resistance, toxicity and cost. The wide-spectrum antimicrobial activity of 2-nitrovinylfuran compounds has been described, as has their activity against Trichomonas vaginalis and other protozoa. Thus, the aim of this study was to test the antileishmanial activities of six 2-nitrovinylfurans in vitro and in a murine model of leishmaniasis. Minimum parasiticide concentration (MPC) and 50% inhibitory concentration (IC50) values for these compounds against the promastigotes of Leishmania amazonensis, Leishmania infantum and Leishmania braziliensis were determined, as were the efficacies of two selected compounds in an experimental model of cutaneous leishmaniasis (CL) caused by L. amazonensis in BALB/c mice. All of the compounds were active against the promastigotes of the three Leishmania species tested. IC50 and MPC values were in the ranges of 0.8-4.7 µM and 1.7-32 µM, respectively. The compounds 2-bromo-5-(2-bromo-2-nitrovinyl)-furan (furvina) and 2-bromo-5-(2-methyl-2-nitrovinyl)-furan (UC245) also reduced lesion growth in vivo at a magnitude comparable to or higher than that achieved by amphotericin B treatment. The results demonstrate the potential of this class of compounds as antileishmanial agents and support the clinical testing of Dermofural(r) (a furvina-containing antifungal ointment) for the treatment of CL.

Análisis inferencial de las potencialidades de promoción de absorción de una familia de 1-O-alquil gliceroles / Inferable analysis related to promotion of the absorption potentialities from 1-O-alkyl glycerol family

La interrelación entre las propiedades físico-químicas y la biodisponibilidad de una familia de 1-O-alquil gliceroles son discutidas, se han utilizado como compuestos de referencia, moléculas que presentan una analogía estructural-funcional con estos compuestos, los cuales han sido reconocidos como agentes promotores clase I, de alta capacidad. El enfoque TOPS-MODE (ModesLab) fue utilizado para estimar los momentos espectrales, con diferentes ponderaciones, como descriptores de las propiedades físico-químicas más relevantes utilizadas en los modelos predictivos de permeabilidad intestinal obtenidos, e interpretar estos en términos de contribución de grupos funcionales de los 1-O-alquil gliceroles. A partir de este análisis se establecieron interpretaciones de tipo inferencial sobre las reales potencialidades teóricas de esta familia para su evaluación perspectiva como agentes promotores de absorción clase I. Este enfoque de tamizaje in sílico asistido por computadora permitió postular que los 1-O-alquil gliceroles, en particular el 1-O-hexadecil glicerol y 1-O-octadecil glicerol, son excelentes candidatos para demostrar su elevada capacidad promotora en estudios in vivo, los que han alcanzado altos niveles porcentuales de biodisponibilidad (> 90 por ciento). Se concluye, según análisis por discriminante, que todos los miembros de la familia presentaron potencialidades para la absorción gastrointestinal.

The interrelation among the physical-chemical properties and the bioavailability of a 1-O-alkyl glycerol family is discussed. As reference compounds we used molecules presenting a structural-functional similarity with these compounds, which have been recognized as class I high quality promoting agents. TOPS-MODE approach (ModesLab) was used to estimate spectral moments with different weighing as descriptors of the more relevant physical-chemical properties used in the achieved predictive models of intestinal permeability, and its interpretation in terms of contribution of 1-O-alkyl glycerols functional groups of. From this analysis we established inferred interpretations on the theoretical potentials of this family for its prospective evaluation as promoting agents of class I absorption. This computer-assisted in silico screening approach allowed us to call for that 1-O-alkin glycerols, particularly in the 1-O-hexadecyl glycerol, and 1-O-octadecil glycerol, are excellent candidates to demonstrate its high promotion capacity according to in vivo studies, which have gained percentage high levels of bioavailability (> 90 ). We conclude that according a discriminating analysis, all family members had potentials for gastrointestinal absorption.