Chemical Biology and Drug Design p. 1141 - 1155 (2018)
Update date:2022-08-11
Topics:
de Lima Serafim, Vanessa
Félix, Mayara Barbalho
Frade Silva, Daiana Karla
Rodrigues, Klinger Ant?nio da Franca
Andrade, Patrícia Néris
de Almeida, Sinara M?nica Vitalino
de Albuquerque dos Santos, Sanderssonilo
de Oliveira, Jamerson Ferreira
de Lima, Maria do Carmo Alves
Mendon?a-Junior, Francisco Jaime Bezerra
Scotti, Marcus Tullius
de Oliveira, Márcia Rosa
de Moura, Ricardo Olímpio
In this 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 Leishmania (Leishmania) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS01 is not associated with DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 104?m?1. In partial least-squares 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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