RESUMEN

Leishmaniasis and Chagas disease are neglected tropical diseases caused by Trypanosomatidae parasites. Given the numerous limitations associated with current treatments, such as extended treatment duration, variable efficacy, and severe side effects, there is an urgent imperative to explore novel therapeutic options. This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in the fight against Chagas disease and leishmaniasis.

Asunto(s)

Diseño de Fármacos , Leishmania infantum , Pruebas de Sensibilidad Parasitaria , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Relación Dosis-Respuesta a Droga , Antiprotozoarios/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Humanos , Animales , Sulfonas/farmacología , Sulfonas/síntesis química , Sulfonas/química

RESUMEN

Phakopsora pachyrhizi is a biotrophic fungus, causer of the disease Asian Soybean Rust, a severe crop disease of soybean and one that demands greater investment from producers. Thus, research efforts to control this disease are still needed. We investigated the expression of metabolites in soybean plants presenting a resistant genotype inoculated with P. pachyrhizi through the untargeted metabolomics approach. The analysis was performed in control and inoculated plants with P. pachyrhizi using UHPLC-MS/MS. Principal component analysis (PCA) and the partial least squares discriminant analysis (PLS-DA), was applied to the data analysis. PCA and PLS-DA resulted in a clear separation and classification of groups between control and inoculated plants. The metabolites were putative classified and identified using the Global Natural Products Social Molecular Networking platform in flavonoids, isoflavonoids, lipids, fatty acyls, terpenes, and carboxylic acids. Flavonoids and isoflavonoids were up-regulation, while terpenes were down-regulated in response to the soybean-P. pachyrhizi interaction. Our data provide insights into the potential role of some metabolites as flavonoids and isoflavonoids in the plant resistance to ASR. This information could result in the development of resistant genotypes of soybean to P. pachyrhizi, and effective and specific products against the pathogen.