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 Leishmania amazonensis, Leishmania braziliensis, and Leishmania infantum. 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 (13, 16, 18, 19, and 20) 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 20, a brominated derivative, displayed the highest activity (IC50 = 11.70–18.40 μM; SI up to 33.6), followed by compound 19 bearing a trifluoromethyl substituent (IC50 = 17.30–26.70 μM; SI up to 24.6). In assays with infected macrophages, compounds 16, 19, and 13 significantly reduced intracellular amastigote burdens (≥60% reduction), with moderate efficacy against L. braziliensis. Quantum chemical analyses suggest that compounds 13, 16, and 18 may function as reducing agents, while compounds 19 and 20 may act as oxidizing agents in redox reactions. ADMET evaluations indicate that compounds 19 and 20 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 in silico 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.