TY - JOUR
T1 - Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase
AU - Kashif, Muhammad
AU - Chacón-Vargas, Karla Fabiola
AU - López-Cedillo, Julio Cesar
AU - Nogueda-Torres, Benjamín
AU - Paz-González, Alma D.
AU - Ramírez-Moreno, Esther
AU - Agusti, Rosalia
AU - Uhrig, Maria Laura
AU - Reyes-Arellano, Alicia
AU - Peralta-Cruz, Javier
AU - Ashfaq, Muhammad
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/8/5
Y1 - 2018/8/5
N2 - 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.
AB - 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.
KW - Inhibitors
KW - Molecular docking
KW - Phthaloyl
KW - Propionic acid
KW - Trans-sialidase
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85049568232&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.07.005
DO - 10.1016/j.ejmech.2018.07.005
M3 - Artículo
C2 - 30006170
SN - 0223-5234
VL - 156
SP - 252
EP - 268
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -