Pre-clinical evaluation of (2E,5E)-2,5-bis(isoquinolin-5-ylmethylene)-cyclopentanone as a promising leishmanicidal agent.

Leishmaniasis is a neglected tropical disease whose current treatments present several limitations. In this context, the search for new antileishmanial agents remains highly relevant. The aim of this study was to investigate the safety and therapeutic potential of (2E,5E)-2,5-bis(isoquinolin-5-ylmethylene)cyclopentanone (ICP), a bis(arylmethylidene) cycloalkanone, against Leishmania infantum. The antileishmanial activity of ICP was evaluated against intracellular amastigote forms of L. infantum, and the compound exhibited an EC₅₀ value of 22.6 ± 0.17 μM. The cytotoxicity of ICP was also assessed in the human monocytic leukemia cell line THP-1, revealing low toxicity, with a CC₅₀ of 190 ± 2.5 µM and a selectivity index of 8.4. In addition, in vivo studies were performed to investigate acute toxicity and therapeutic efficacy. For the evaluation of acute toxicity in healthy mice, ICP was administered intraperitoneally at a single dose of 100 mg/kg. Under these conditions, no deaths or body weight loss were observed. Moreover, no significant changes were detected in hematological, hepatic, cardiac, or renal parameters in ICP-treated animals when compared with the control group. Therapeutic efficacy was evaluated in L. infantum- infected mice treated intraperitoneally with ICP at doses of 25, 50, and 75 mg/kg/day for 10 consecutive days. A reduction in parasite load (85%) was observed in the liver of treated animals compared with the control group. Overall, these preliminary results indicate that ICP represents an interesting chemical scaffold for further optimization and investigation toward the development of new treatments for leishmaniasis.