Synthesis and Antileishmanial Activity of Cinnamic Acid–Amantadine Amides

A novel series of cinnamic acid-amantadine amides was designed, synthesized, and evaluated for antileishmanial activity against <i>Leishmania amazonensis</i>, <i>Leishmania braziliensis</i>, and <i>Leishmania infantum</i>. The target compounds were obtained via amidation of cinnamic acid derivatives with amantadine, using EDC as a coupling reagent, and their structures were confirmed by IR, NMR, and HRMS analyses. Preliminary screening identified five derivatives (<b>13</b>, <b>16</b>, <b>18</b>, <b>19</b>, and <b>20</b>) with >90% inhibition of promastigote viability at micromolar concentrations. These five compounds exhibited IC₅₀ values in the low micromolar range and favorable selectivity indices (SI > 9). Notably, compound <b>20</b>, a brominated derivative, displayed the highest activity (IC₅₀ = 11.70-18.40 μM; SI up to 33.6), followed by compound <b>19</b> bearing a trifluoromethyl substituent (IC₅₀ = 17.30-26.70 μM; SI up to 24.6). In assays with infected macrophages, compounds <b>16</b>, <b>19</b>, and <b>13</b> significantly reduced intracellular amastigote burdens (≥60% reduction), with moderate efficacy against <i>L. braziliensis</i>. Quantum chemical analyses suggest that compounds <b>13</b>, <b>16</b>, and <b>18</b> may function as reducing agents, while compounds <b>19</b> and <b>20</b> may act as oxidizing agents in redox reactions. ADMET evaluations indicate that compounds <b>19</b> and <b>20</b> possess higher hydrophobicity (reflected by the highest LogP values) and lower topological polar surface area (TPSA) than the other compounds, implying enhanced membrane permeability. These <i>in silico</i> findings suggest that increased lipophilicity and the presence of electron-withdrawing groups enhance potency, likely by improving membrane permeability and redox activity. Overall, these results highlight cinnamic acid-amantadine hybrids as promising scaffolds for developing new antileishmanial agents with improved safety profiles.