Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 μM against L. infantum amastigote forms and CC50 value superior to 500 μM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 μM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.

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Introduction:The exacerbated generation of advanced glycation end products (AGEs) triggers the onset of diabetic complications associated with hyperglycemia. The search for natural bioactive compounds that can inhibit AGE formation has gained immense interest. Quercetin and its glycoside derivative, rutin, are powerful antioxidants. They have been studied due to their potential to mitigate the disturbances observed in diabetes; however, studies comparing their antiglycation effects are limited. The aim of the present study was to compare the in vitro antiglycation potentials of quercetin and rutin. Methods: The in vitro model system of protein glycation was applied using bovine serum albumin (10 mg/mL) incubated with glucose (0.5 M) in the absence or presence of aminoguanidine (1 mM, prototype anti-AGE agent), metformin (1 mM), quercetin (100, 50, or 12.5 µM), or rutin (100, 50, or 12.5 µM). Before initiating incubations (day 0) and after 10, 20, and 30 days, aliquots were assayed for fluorescent AGEs. Markers of amino acid oxidation (dityrosine, N'-formylkynurenine, kynurenine), protein carbonyl groups (PCO), and protein crosslink formation were assessed after 30 days. Results: Both quercetin and rutin inhibited the formation of AGEs and decreased the PCO levels in a concentration-dependent manner, and moreover, the effect of rutin was more prominent than that of quercetin. Quercetin and rutin also decreased the formation of amino acid oxidation products and protein crosslinks; the best effects were observed in incubations with rutin. Conclusion: Rutin exhibited the most potent antiglycation and antioxidant activities, which may be attributed to the minor occurrence of interactions between albumin and rutin, making rutinnoside more available to exert its effects.

Long-term hyperglycemia maintenance is responsible for increased protein glycation and formation of advanced glycation end products (AGEs), both are associated with the onset of diabetes mellitus complications. Efforts have been made to discover new agents having antiglycation potential. The aim of this study was to investigate the effects of the hydroethanolic extract and the ethyl acetate and methanolic fractions of Simaba trichilioides roots on the formation of AGEs. In an in vitro model system of protein glycation, incubations with hydroethanolic extract, ethyl acetate or methanolic fractions of S. trichilioides decreased the fluorescent AGEs, and markers of tyrosine and tryptophan oxidation. Protein crosslinking was reduced in the presence of the ethyl acetate fraction of S. trichilioides. Simaba trichilioides roots seem to be a promising source of compounds having ability to prevent glycoxidation changes, with potential applications in complementary therapies for management of diabetic complications.

Since lycopene has antioxidant activity, its combination with metformin may be useful to contrast diabetic complications related to oxidative stress. This study aimed to investigate the effects of metformin combined with lycopene on high-fat diet (HFD)-induced obese mice. Seventy-two C57BL-6J mice were divided into six groups: C (control diet-fed mice), H (HFD-fed mice for 17 weeks), H-V (HFD-fed mice treated with vehicle), H-M (HFD-fed mice treated with 50 mg/kg metformin), H-L (HFD-fed mice treated with 45 mg/kg lycopene), and H-ML (HFD-fed mice treated with 50 mg/kg metformin + 45 mg/kg lycopene). Treatments were administered for 8 weeks. Glucose tolerance, insulin sensitivity, fluorescent AGEs (advanced glycation end products), TBARS (thiobarbituric acid-reactive substances), and activities of antioxidant enzymes paraoxonase-1 (PON-1; plasma), superoxide dismutase, catalase and glutathione peroxidase (liver and kidneys) were determined. Metformin plus lycopene reduced body weight; improved insulin sensitivity and glucose tolerance; and decreased AGEs and TBARS in plasma, liver and kidneys. Combined therapy significantly increased the activities of antioxidant enzymes, mainly PON-1. Lycopene combined with metformin improved insulin resistance and glucose tolerance, and caused further increases in endogenous antioxidant defenses, arising as a promising therapeutic strategy for combating diabetic complications resulting from glycoxidative stress.