Indazole Derivatives Against Murine Cutaneous Leishmaniasis

Abstract

Background/Objectives: Leishmaniasis is a zoonotic and anthropozoonotic disease with significant public health impact worldwide and is classified as a neglected tropical disease. The search for new affordable treatments, particularly oral and/or topical ones that are easy to administer and have fewer side effects, remains a priority for the scientific community in this field of research. In previous investigations, 3-alkoxy-1-benzyl-5-nitroindazole derivatives showed remarkable in vitro results against Leishmania species, and predictions of absorption, distribution, metabolism, excretion, and toxicity properties, as well as pharmacological scores, of the compounds classified as active were superior to those of amphotericin B, indicating their potential as candidates for in vivo studies. Therefore, the aim of the present study was to evaluate the in vivo antileishmanial activity of the indazole derivatives NV6 and NV16. Methods: The compounds were administered intralesionally at concentrations of 10 and 5 mg/kg in a BALB/c mouse model of cutaneous leishmaniasis caused by Leishmania amazonensis. To evaluate the efficacy of the compounds, indicators such as lesion size, ulcer area, lesion weight, and parasitic load were determined. Amphotericin B was used as a positive control. Results: The compound NV6 showed leishmanicidal activity comparable to that observed with amphotericin B, with a significant reduction in lesion development and parasite load, while NV16 caused a reduction in ulcer area. Conclusions: These results provide strong evidence for the antileishmanial activity of NV6 and support future studies to improve its pharmacokinetic profile, as well as the investigation of combination therapies with other chemotherapeutic agents currently in use.

Keywords: 3-alkoxy-1-benzyl-5-nitroindazole; BALB/c mice; Leishmania amazonensis; cutaneous leishmaniasis; in vivo antileishmanial activity; neglected tropical diseases.

Figure 1

Structure of 3-alkoxy-1-benzyl-5-nitroindazole derivatives NV6 and NV16.

Figure 2

Evolution of body weight in the treatment groups from the start to the end of the experiment.

Figure 3

Effect of treatment with NV6 and NV16 at doses of 10 mg/kg and 5 mg/kg of live weight on lesion size (*: p < 0.05, **: p < 0.01).

Figure 4

Effect of treatment with NV6 and NV16 at doses of 10 mg/kg and 5 mg/kg of live weight on the ulcer area (*: p < 0.05, compared to the amphotericin B group).

Figure 5

Effect of treatment on lesion weight (a) and parasite load (b) one week after completion of treatment. (*: p < 0.05, compared to the control group). Bars represent geometric means, and error lines indicate minimum and maximum values. Data labels indicate the percent reduction in parasite load relative to untreated control mice.