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 , , and . 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 (, , , , and ) with >90% inhibition of promastigote viability at micromolar concentrations. These five compounds exhibited IC values in the low micromolar range and favorable selectivity indices (SI > 9). Notably, compound , a brominated derivative, displayed the highest activity IC = 11.70-18.40 μM; SI up to 33.6, followed by compound bearing a trifluoromethyl substituent IC = 17.30-26.70 μM; SI up to 24.6. In assays with infected macrophages, compounds , , and significantly reduced intracellular amastigote burdens (≥60% reduction), with moderate efficacy against . Quantum chemical analyses suggest that compounds , , and may function as reducing agents, while compounds and may act as oxidizing agents in redox reactions. ADMET evaluations indicate that compounds and 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 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.