Efficacy and Pharmacokinetics of Guanidine Derivative LQOF-G2 in an In Vivo Leishmania (Viannia) braziliensis Model

Background/Objectives: Due to their toxicity and the limited efficacy of current therapies, Leishmaniases represent a major public health challenge. The search for new treatments is urgent. LQOF-G2 is a synthetic guanidine compound whose in vitro leishmanicidal potential has already been investigated by our group. The present study evaluates the in vivo efficacy, safety-related parameters, treatment-associated cytokine responses, and pharmacokinetic (PK) properties of the novel guanidine derivative LQOF-G2. Methods: Golden hamsters infected with Leishmania (Viannia) braziliensis were treated with LQOF-G2 (5 and 10 mg/kg, i.p.). Pharmacokinetic characterization was performed in BALB/c mice following intravenous and intraperitoneal administration. Results: Treatment with LQOF-G2 significantly reduced cutaneous lesion size and parasite burden at both the site of infection (up to 98.6 ± 0.8%) and in the lymph nodes (up to 99.7 ± 0.3%). No marked alterations were observed in the biochemical and hematological parameters evaluated at the tested doses. Treatment was associated with increased TNF-α and IFN-γ responses and reduced IL-10 levels following ex vivo antigen stimulation, consistent with a more pro-inflammatory/type-1-associated cytokine profile. Because murine cytokine ELISA reagents were used with golden hamster samples without independent species-specific analytical validation, these findings were considered exploratory and supportive rather than quantitatively validated evidence of an immunomodulatory mechanism. Pharmacokinetic characterization in BALB/c mice revealed moderate clearance (46 ± 4 mL/min/kg), a relatively large apparent volume of distribution (Vdss = 11 ± 1 L/kg), and a long elimination half-life (6.8 ± 0.4 h) following intravenous administration. After intraperitoneal administration, rapid absorption (Tmax = 0.25 h) and an absolute bioavailability of 44% were observed. Conclusions: Overall, these findings support LQOF-G2 as a candidate for further preclinical investigation in cutaneous leishmaniasis.