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Current therapeutic ways adopted for the treatment of leishmaniasis are toxic and expensive including parasite resistance is a growing problem. Given this scenario, it is urgent to explore treatment alternatives for leishmaniasis. The aim of this study was to evaluate the effect of 3-phenyl-lawsone (3-PL) naphthoquinone on Leishmania (Viannia) braziliensis infection, both in vitro and in vivo, using two local routes of administration: subcutaneous (higher dose) and tattoo (lower dose). In vitro 3-PL showed low toxicity for macrophages (CC50 >3200 µM/48h) and activity against intracellular amastigotes (IC50 = 193 ± 19 µM/48h) and promastigotes (IC50 = 116 ± 26 µM/72h), in which induced increased ROS generation. Additionally, 3-PL up-regulated the production of cytokines such as tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-6 (IL-6) and IL-10 in infected macrophages. However, the anti-amastigote action was independent of nitric oxide production. Treatment of hamsters infected with L. (V.) braziliensis from one week after infection with 3-PL by subcutaneous (25 µg/Kg) or tattooing (2.5 µg/Kg) route, during 3 weeks (3 times/week) or 2 weeks (2 times/week) significantly decreased the parasite load (p

Leishmaniasis is a parasitic disease caused by several species of intracellular protozoa of the genus Leishmania that present manifestations ranging from cutaneous ulcers to the fatal visceral form. Leishmania Viannia braziliensis is an important species associated with American tegumentary leishmaniasis and the main agent in Brazil, with variable sensitivity to available drugs. The search for new therapeutic alternatives to treat leishmaniasis is an urgent need, especially for endemic countries. Not only is quercetin well known for its antioxidant activity in radical scavenging but also several other biological effects are described, including anti-inflammatory, antimicrobial, and pro-oxidant activities. This study aimed to investigate the flavonoid quercetin’s therapeutic potential in L. (V.) braziliensis infection. Quercetin showed antiamastigote (IC50 of 21 ± 2.5 µM) and antipromastigote (25 ± 0.7 µM) activities and a selectivity index of 22. The treatment of uninfected or L. (V.) braziliensis–infected macrophages with quercetin increased reactive oxygen species (ROS)/H202 generation without altering Nitric Oxide (NO) production. Oral treatment with quercetin of infected hamsters, starting at 1 week of infection for 8 weeks, reduced the lesion thickness (p > 0.01) and parasite load (p > 0.001). The results of this study suggest that the antiamastigote activity of the flavonoid quercetin in vitro is associated, at least in part, with the modulation of ROS production by macrophages. The efficacy of oral quercetin treatment in hamsters infected with L. (V.) braziliensis was presented for the first time and shows its promising therapeutic potential.

Pentavalent antimonials have saved the lives of thousands of Leishmania-infected patients more than seventy years but, unfortunately, they are highly toxic and require parenteral delivery. Therefore, the search for safer and orally delivered alternative is a need. This paper describes the antileishmanial properties of PMIC4, a novel hydroxyethylpiperazine analogue. PMIC4 showed potent activity against intracellular amastigotes of Leishmania amazonensis, with IC50 of 1.8 μM and selectivity index higher than 100-fold, calculated in relation to the toxicity on the host cell. Following laboratory animal welfare policies, we analyzed the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and calculated the Lipinski’s rule of five of PMIC4 before proceeding to in vivo tests. PMIC4 satisfied Lipinski’s rule of five and presented high probability of human intestinal absorption, suggesting a good chance of druglikeness and oral bioavailability. For in vivo studies, PMIC4 was administered via intralesional injection (3.4 mg/kg/day, three times a week) or orally (34.0 mg/kg/day, five times a week) to L. amazonensis-infected BALB/c mice throughout the 98 day experiments. At the end of the treatment period, serum markers of toxicity were measured. When administered orally, PMIC4 controlled the lesions in L. amazonensis-infected BALB/c mice without altering serological markers of toxicity. These results demonstrate that PMIC4 is a promising molecular scaffold, orally effective against experimental leishmaniasis.