Synthesis and Antileishmanial Activity of Cinnamic Acid–Amantadine Amides

TL;DR

Scientists created new compounds by combining cinnamic acid and amantadine, which showed strong antileishmanial activity and could lead to better treatments for leishmaniasis.

Contribution

The study introduces novel cinnamic acid–amantadine amides with potent antileishmanial activity and improved pharmacological properties.

Findings

Five compounds showed >90% inhibition of promastigote viability at micromolar concentrations.

Compound 20 had the highest activity with an IC50 of 11.70–18.40 μM and a selectivity index up to 33.6.

Compounds 19 and 20 exhibited higher hydrophobicity and lower polar surface area, suggesting better membrane permeability.

Abstract

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.

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