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Arginase is a metalloenzyme that plays a central role in <i>Leishmania</i> infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as <i>Leishmania amazonensis</i> arginase inhibitors. Here, we describe the inhibition of arginase in <i>L. amazonensis</i> by rosmarinic acid analogs (<b>1–7</b>) and new caffeic acid-derived amides (<b>8–10</b>). Caffeic acid esters and amides were produced by means of an engineered synthesis in <i>E. coli</i> and tested against <i>L. amazonensis</i> arginase. New amides (<b>8–10</b>) were biosynthesized in <i>E. coli</i> cultured with 2 mM of different combinations of feeding substrates. The most potent arginase inhibitors showed Ki(s) ranging from 2 to 5.7 μM. Compounds <b>2–4</b> and <b>7</b> inhibited <i>L. amazonensis</i> arginase (L-ARG) through a noncompetitive mechanism whilst compound <b>9</b> showed a competitive inhibition. By applying an in silico protocol, we determined the binding mode of compound <b>9</b>. The competitive inhibitor of L-ARG targeted the key residues within the binding site of the enzyme, establishing a metal coordination bond with the metal ions and a series of hydrophobic and polar contacts supporting its micromolar inhibition of L-ARG. These results highlight that dihydroxycinnamic-derived compounds can be used as the basis for developing new drugs using a powerful tool based on the biosynthesis of arginase inhibitors.