Flavonoids have demonstrated in vivo and in vitro leishmanicidal, trypanocidal, antioxidant, and prooxidant properties. The chemotherapy of trypanosomiasis and leishmaniasis lacks efficacy, presents high toxicity, and is related to the development of drug resistance. Thus, a series of 40 flavonoids were investigated with the purpose of correlating these properties via structure and activity analyses based on integrated networks and QSAR models. The classical groups for the antioxidant activity of flavonoids were combined in order to explain the influence of antioxidant and prooxidant activities on the antiparasitic properties. These analyses become useful for the development of efficient treatments for leishmaniasis and trypanosomiasis. Finally, the dual activity of flavonoids presenting both anti- and prooxidant activities revealed that the existence of a balance between these two features could be important to the development of adequate therapeutic strategies.

Introduction Plants have been considered a promising source for discovering new compounds with pharmacological activities. The Fabaceae family comprises a large variety of species that produce substances with diverse therapeutic potential, including anti‐inflammatory activity. The limitations of current anti‐inflammatories generate the need to research new anti‐inflammatory structures with higher efficacy as well as develop methods for screening multiple samples, reliably and ethically, to assess such therapeutic properties. Objective Validate and apply a quantification method for prostaglandin E2 (PGE2) production from an ex vivo assay in human blood in order to screen anti‐inflammatory activity present in many Fabaceae species extracts. Methods Human blood was incubated with extracts from 47 Fabaceae species. After lipopolysaccharide (LPS)‐induced inflammation, PGE2 was quantified in the plasma by liquid chromatography with tandem mass spectrometry (LC–MS/MS). The extracts that presented PGE2 production inhibition were further assessed through in vivo assay and then chemically characterised through an analysis of ultra‐performance liquid chromatography electrospray ionisation quadrupole time‐of‐flight tandem mass spectrometry (UPLC‐ESI‐QTOF‐MS2) data. Results The new ex vivo anti‐inflammatory assay showed that five out of the 47 Fabaceae species inhibited PGE2 production. Results from an in vivo assay and the metabolic profile of the active extracts supported the anti‐inflammatory potential of four species. Conclusion The quantification method for PGE2 demonstrated fast, sensitive, precise, and accurate results. The new ex vivo anti‐inflammatory assay comprised a great, reliable, and ethical approach for the screening of a large number of samples before an in vivo bioassay. Additionally, the four active extracts in both ex vivo and in vivo assays may be useful for the development of more efficient anti‐inflammatory drugs.

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Metabolomics approaches have become fundamental strategies for the analysis of complex mixtures, guiding the isolation of target compounds by focusing on unpublished or promising pharmacological properties. The discovery of novel anti-inflammatory agents is important due to several limitations regarding their potency, efficacy, and adverse effects. Thus, novel anti-inflammatory candidates are essential, aiming to find agents with better mechanisms of action. In this context, extracts from Poincianella pluviosa var. peltophoroides demonstrated significant in vivo anti-inflammatory potential. Thus, metabolomics analysis based on UHPLC-UV-HRFTMS data was performed for the identification of biomarkers with anti-inflammatory properties. Metabolomics-guided chromatographic process led to the isolation of novel compounds 4‴-methoxycaesalpinioflavone and 7-methoxycaesalpinioflavone, as well as known derivatives rhuschalcone VI and caesalpinioflavone. Isolated compounds caused edema inhibition and neutrophil recruitment. Two of them showed better efficacy than reference drugs (indomethacin and dexamethasone). Results of in vivo experiments corroborated those obtained through metabolomics and statistical analyses guiding the isolation of substances of interest.

A series of novel benzophenone derivatives containing a thiazole heterocyclic nucleus were designed by molecular hybridization. Molecular docking studies have demonstrated the inhibitory potential of the designed compounds against cyclooxygenase (COX) isoenzymes. These compounds were synthesized, characterized, and evaluated for their anti-inflammatory properties by the croton oil-induced ear edema assay to examine their effect on both prostaglandin (PG) production and neutrophils recruitment. The thiazole derivatives displayed a potent effect in terms of reducing ear edema. The analysis suggested that the presence of 4-phenyl-2-hydrazinothiazole and the absence of C4′-OCH3 on the benzophenone derivative structure are strongly related to the inhibition of PG production. In addition, the derivatives 2e, 3a and 3c concomitantly inhibit PG production and neutrophil recruitment, which may be a mechanism of action better than of common NSAIDs due to their inability to inhibit the neutrophil recruitment. Thus, these compounds can be considered as potential lead compounds toward the development of new anti-inflammatory drugs with an innovating mechanism of action.