Perillic Acid Synergizes With the Miltefosine Leishmanicidal Effect Against Leishmania amazonensis

ABSTRACT

Perillic acid (PA), a monocyclic monoterpene derived from limonene, was evaluated for its leishmanicidal activity alone and in combination with miltefosine, as well as in its microemulsion‐based formulation. PA demonstrated synergistic activity with miltefosine and was effective against both promastigote and amastigote forms of Leishmania amazonensis . Its anti‐amastigote effect was independent of nitric oxide production but was partially associated with reduced arginase activity in stimulated macrophages. In a murine model of cutaneous leishmaniasis, topical treatment with a PA‐loaded microemulsion resulted in a marked reduction in parasite burden, achieving a 99% reduction in L. amazonensis infections. PA also showed efficacy in vivo across different administration routes and showed significant skin permeation when formulated in a microemulsion. These findings highlight PA as a promising leishmanicidal agent and support its potential application in the treatment of cutaneous leishmaniasis.