Cinnamides Target Leishmania amazonensis Arginase Selectively

Area of Science:

• Medicinal Chemistry
• Parasitology
• Computational Chemistry

Background:

• *Leishmania amazonensis* causes leishmaniasis, a neglected tropical disease.
• Arginase is a validated drug target for treating leishmaniasis.
• Previous studies identified natural compounds as inhibitors of *Leishmania* arginase (L-ARG).

Purpose of the Study:

• To evaluate synthetic cinnamides as potential inhibitors of L-ARG.
• To investigate the selectivity of these compounds against L-ARG over human arginase.
• To explore the mechanism of L-ARG inhibition using computational methods.

Main Methods:

• Synthesis of cinnamides.
• Enzyme inhibition assays for L-ARG and human arginase.
• Antiparasitic activity testing against *L. amazonensis* promastigotes.
• Molecular docking and computational modeling.

Main Results:

• Caffeic acid phenethyl amide (CAPA) showed 9-fold increased potency against L-ARG (IC50 = 6.9 μM) compared to human arginase.
• Other cinnamides, including compound 15 (IC50 = 1.3 μM), were potent L-ARG inhibitors with selectivity over human arginase.
• CAPA exhibited inhibitory activity against *L. amazonensis* promastigotes (IC50 = 80 μM).
• Computational studies provided insights into the selective inhibition mechanism.

Conclusions:

• Cinnamides, particularly those with cinnamoyl or 3,4-hydroxy cinnamoyl moieties, are promising scaffolds for developing selective L-ARG inhibitors.
• These compounds represent a potential starting point for novel antileishmanial drug design.
• Selective L-ARG inhibition offers a viable strategy for combating leishmaniasis.