New Thiophene-Acridine Compounds: Synthesis, Antileishmanial Activity, DNA Binding, Chemometric and Molecular Docking Studies

Abstract

In the present study, we synthesized eight new compounds containing the 2-amino-cycloalkyl[b]thiophene and acridine moieties (ACT₀₁ and ACS₀₁-ACS₀₇). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS₀₁ and ACS₀₂ derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC₅₀ values of 9.60±3.19 and 10.95±3.96 μM. Additionally, these two derivatives were effective against antimony-resistant L. (L.) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS₀₁ is not associated to DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 10⁴ M⁻¹. In partial least-squares (PLS) studies, it was observed that the most active compounds (ACS₀₁ and ACS₀₂) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene-acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene-acridine derivatives are promising molecules as potential drug candidates.

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The new compounds presented antileishmanial activity, with better performance than the reference drugs (ACS₀₁ and ACS₀₂), without to present human erythrocyte cytotoxicity.

The best compound ACS₀₁ interacted with DNA. However, the antileishmanial activity of ACS₀₁ is not associated to DNA fragmentation of the promastigote forms.

Theoretical studies showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. In addition, the docking molecular studies showed interactions between thiophene-acridine derivatives and the active site of pyruvate kinase enzyme.

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