Synthesis and Antileishmanial Evaluation of <i>N</i>-Phenyl-2-phenoxyacetamides Derived from Carvacrol

Leishmaniasis, caused by protozoa of the genus <i>Leishmania</i> and transmitted by sandflies, remains prevalent in underdeveloped countries. The disease manifests in three clinical forms: cutaneous, mucocutaneous, and visceral, the latter being fatal without adequate treatment. Current therapies, including pentavalent antimonials, have important limitations, such as high toxicity and reduced efficacy. This study investigates synthetic compounds derived from carvacrol as potential therapeutic alternatives. Carvacrol serves as a precursor for the synthesis of carvacroxyacetic acid, a key intermediate in producing <i>N</i>-phenyl-2-phenoxyacetamides. Ten novel molecules were synthesized with yields ranging from 11% to 60%. All synthesized compounds were characterized using mass spectrometry, ¹H NMR and ¹³C NMR. Additionally, the structure of compound <b>9</b> (C₁₈H₂₀FNO₂) was confirmed by X-ray crystallography. Cytotoxicity assays with macrophages and Vero cells revealed that all ten <i>N</i>-phenyl-2-phenoxyacetamides exhibited low or no toxicity at the tested concentrations. Compounds <b>5</b> and <b>7</b> demonstrated significant antileishmanial activity against <i>Leishmania braziliensis</i>, outperforming both the untreated control and the precursor carvacroxyacetic acid (CA). Furthermore, their efficacy against the parasite exceeded for the activity of pure carvacrol reported in the literature. These findings highlight the significant potential of these compounds and emphasize the importance of further studies to elucidate their mechanisms of action and explore broader therapeutic applications.