Leishmaniasis is a significant public health concern, affecting millions and causing substantial mortality, thus urgently requiring more effective and safer treatments. This study explored the potential of 33 novel -acylhydrazone-derived compounds against parasites, focusing on their inhibition of the arginase enzyme and promastigote growth. Compounds and showed over 90% inhibitory activity against promastigote cultures after 72 h of treatment. Compound showed an IC of 10.5 µM (9.4-11.8 µM), while compound exhibited an IC of 42.8 µM (41.3-44.4 µM). The antipromastigote effects of these compounds highlight their potential for further new drug design. These findings offer a promising starting point for addressing the pressing need for new therapeutic options against leishmaniasis. In addition, we used web-based tools to predict the compounds' toxicity and pharmacokinetic parameters. Despite the lack of inhibition against the arginase enzyme, further investigation into the mechanisms of action of these compounds and in vivo efficacy could contribute to the development of safer and more effective treatments for this neglected tropical disease.