Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase

Muhammad Kashif, Karla Fabiola Chacón-Vargas, Julio Cesar López-Cedillo, Benjamín Nogueda-Torres, Alma D. Paz-González, Esther Ramírez-Moreno, Rosalia Agusti, Maria Laura Uhrig, Alicia Reyes-Arellano, Javier Peralta-Cruz, Muhammad Ashfaq, Gildardo Rivera

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

13 Citas (Scopus)

Resumen

In the last two decades, trans-sialidase of Trypanosoma cruzi (TcTS) has been an important pharmacological target for developing new anti-Chagas agents. In a continuous effort to discover new potential TcTS inhibitors, 3-amino-3-arylpropionic acid derivatives (series A) and novel phthaloyl derivatives (series B, C and D) were synthesized and molecular docking, TcTS enzyme inhibition and determination of trypanocidal activity were carried out. From four series obtained, compound D-11 had the highest binding affinity value (−11.1 kcal/mol) compared to reference DANA (−7.8 kcal/mol), a natural ligand for TS enzyme. Furthermore, the 3D and 2D interactions analysis of compound D-11 showed a hydrogen bond, π-π stacking, π-anion, hydrophobic and Van der Waals forces with all important amino acid residues (Arg35, Arg245, Arg314, Tyr119, Trp312, Tyr342, Glu230 and Asp59) on the active site of TcTS. Additionally, D-11 showed the highest TcTS enzyme inhibition (86.9% ± 5) by high-performance ion exchange chromatography (HPAEC). Finally, D-11 showed better trypanocidal activity than the reference drugs nifurtimox and benznidazole with an equal % lysis (63 ± 4 and 65 ± 2 at 10 μg/mL) and LC50 value (52.70 ± 2.70 μM and 46.19 ± 2.36 μM) on NINOA and INC-5 strains, respectively. Therefore, D-11 is a small-molecule with potent TcTS inhibition and a strong trypanocidal effect that could help in the development of new anti-Chagas agents.

Idioma originalInglés
Páginas (desde-hasta)252-268
Número de páginas17
PublicaciónEuropean Journal of Medicinal Chemistry
Volumen156
DOI
EstadoPublicada - 5 ago. 2018

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