Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase
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 derivativ...
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_02235234_v156_n_p252_Kashif |
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todo:paper_02235234_v156_n_p252_Kashif |
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dspace |
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Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
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Inhibitors Molecular docking Phthaloyl Propionic acid Trans-sialidase Trypanosoma cruzi 2 [2 carboxy 1 (2 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 ethylphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 hydroxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 methoxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 tolyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 ethylphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 hydroxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 methoxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (4 ethylphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 hydroxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 methoxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (naphthalen 2 yl)propanoic acid 3 amino 3 (4 ethylphenyl)propanoic acid 3 amino 3 (4 hydroxyphenyl)propanoic acid 3 amino 3 (4 methoxyphenyl)propanoic acid 3 amino 3 (4 nitrophenyl)propanoic acid 3 amino 3 (4 tolyl)propanoic acid 3 deoxy 2,3 didehydro n acetylneuraminic acid antitrypanosomal agent benznidazole nifurtimox phthaloyl derivative propionic acid derivative sialidase inhibitor unclassified drug unindexed drug antitrypanosomal agent glycoprotein propionic acid derivative sialidase trans-sialidase Article biological activity controlled study crystal structure drug structure drug synthesis enzyme inhibition hydrogen bond ion exchange chromatography LC50 lysis molecular docking nonhuman sialylation Trypanosoma cruzi amination antagonists and inhibitors Chagas disease chemistry drug design drug effect enzymology human metabolism molecular docking parasitology structure activity relation Trypanosoma cruzi Amination Chagas Disease Drug Design Glycoproteins Humans Molecular Docking Simulation Neuraminidase Propionates Structure-Activity Relationship Trypanocidal Agents Trypanosoma cruzi |
| spellingShingle |
Inhibitors Molecular docking Phthaloyl Propionic acid Trans-sialidase Trypanosoma cruzi 2 [2 carboxy 1 (2 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 ethylphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 hydroxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 methoxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 tolyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 ethylphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 hydroxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 methoxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (4 ethylphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 hydroxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 methoxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (naphthalen 2 yl)propanoic acid 3 amino 3 (4 ethylphenyl)propanoic acid 3 amino 3 (4 hydroxyphenyl)propanoic acid 3 amino 3 (4 methoxyphenyl)propanoic acid 3 amino 3 (4 nitrophenyl)propanoic acid 3 amino 3 (4 tolyl)propanoic acid 3 deoxy 2,3 didehydro n acetylneuraminic acid antitrypanosomal agent benznidazole nifurtimox phthaloyl derivative propionic acid derivative sialidase inhibitor unclassified drug unindexed drug antitrypanosomal agent glycoprotein propionic acid derivative sialidase trans-sialidase Article biological activity controlled study crystal structure drug structure drug synthesis enzyme inhibition hydrogen bond ion exchange chromatography LC50 lysis molecular docking nonhuman sialylation Trypanosoma cruzi amination antagonists and inhibitors Chagas disease chemistry drug design drug effect enzymology human metabolism molecular docking parasitology structure activity relation Trypanosoma cruzi Amination Chagas Disease Drug Design Glycoproteins Humans Molecular Docking Simulation Neuraminidase Propionates Structure-Activity Relationship Trypanocidal Agents Trypanosoma cruzi Kashif, M. Chacón-Vargas, K.F. López-Cedillo, J.C. Nogueda-Torres, B. Paz-González, A.D. Ramírez-Moreno, E. Agusti, R. Uhrig, M.L. Reyes-Arellano, A. Peralta-Cruz, J. Ashfaq, M. Rivera, G. Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase |
| topic_facet |
Inhibitors Molecular docking Phthaloyl Propionic acid Trans-sialidase Trypanosoma cruzi 2 [2 carboxy 1 (2 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 ethylphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 hydroxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 methoxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 tolyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 ethylphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 hydroxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 methoxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (4 ethylphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 hydroxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 methoxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (naphthalen 2 yl)propanoic acid 3 amino 3 (4 ethylphenyl)propanoic acid 3 amino 3 (4 hydroxyphenyl)propanoic acid 3 amino 3 (4 methoxyphenyl)propanoic acid 3 amino 3 (4 nitrophenyl)propanoic acid 3 amino 3 (4 tolyl)propanoic acid 3 deoxy 2,3 didehydro n acetylneuraminic acid antitrypanosomal agent benznidazole nifurtimox phthaloyl derivative propionic acid derivative sialidase inhibitor unclassified drug unindexed drug antitrypanosomal agent glycoprotein propionic acid derivative sialidase trans-sialidase Article biological activity controlled study crystal structure drug structure drug synthesis enzyme inhibition hydrogen bond ion exchange chromatography LC50 lysis molecular docking nonhuman sialylation Trypanosoma cruzi amination antagonists and inhibitors Chagas disease chemistry drug design drug effect enzymology human metabolism molecular docking parasitology structure activity relation Trypanosoma cruzi Amination Chagas Disease Drug Design Glycoproteins Humans Molecular Docking Simulation Neuraminidase Propionates Structure-Activity Relationship Trypanocidal Agents Trypanosoma cruzi |
| description |
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. © 2018 Elsevier Masson SAS |
| format |
JOUR |
| author |
Kashif, M. Chacón-Vargas, K.F. López-Cedillo, J.C. Nogueda-Torres, B. Paz-González, A.D. Ramírez-Moreno, E. Agusti, R. Uhrig, M.L. Reyes-Arellano, A. Peralta-Cruz, J. Ashfaq, M. Rivera, G. |
| author_facet |
Kashif, M. Chacón-Vargas, K.F. López-Cedillo, J.C. Nogueda-Torres, B. Paz-González, A.D. Ramírez-Moreno, E. Agusti, R. Uhrig, M.L. Reyes-Arellano, A. Peralta-Cruz, J. Ashfaq, M. Rivera, G. |
| author_sort |
Kashif, M. |
| title |
Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase |
| title_short |
Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase |
| title_full |
Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase |
| title_fullStr |
Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase |
| title_full_unstemmed |
Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase |
| title_sort |
synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of trypanosoma cruzi trans-sialidase |
| url |
http://hdl.handle.net/20.500.12110/paper_02235234_v156_n_p252_Kashif |
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1782024211755171840 |
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todo:paper_02235234_v156_n_p252_Kashif2023-10-03T15:11:13Z Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase Kashif, M. Chacón-Vargas, K.F. López-Cedillo, J.C. Nogueda-Torres, B. Paz-González, A.D. Ramírez-Moreno, E. Agusti, R. Uhrig, M.L. Reyes-Arellano, A. Peralta-Cruz, J. Ashfaq, M. Rivera, G. Inhibitors Molecular docking Phthaloyl Propionic acid Trans-sialidase Trypanosoma cruzi 2 [2 carboxy 1 (2 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 ethylphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 hydroxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 methoxyphenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 nitrophenyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 2 [2 carboxy 1 (4 tolyl)ethyl] 1,3 dioxoisoindoline 5 carboxylic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 ethylphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 hydroxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 methoxyphenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (4 ethylphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 hydroxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (4 methoxyphenyl) 3 (5 methyl 1,3 dioxoisoindolin 2 yl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 nitrophenyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (4 tolyl)propanoic acid 3 (5 methyl 1,3 dioxoisoindolin 2 yl) 3 (naphthalen 2 yl)propanoic acid 3 amino 3 (4 ethylphenyl)propanoic acid 3 amino 3 (4 hydroxyphenyl)propanoic acid 3 amino 3 (4 methoxyphenyl)propanoic acid 3 amino 3 (4 nitrophenyl)propanoic acid 3 amino 3 (4 tolyl)propanoic acid 3 deoxy 2,3 didehydro n acetylneuraminic acid antitrypanosomal agent benznidazole nifurtimox phthaloyl derivative propionic acid derivative sialidase inhibitor unclassified drug unindexed drug antitrypanosomal agent glycoprotein propionic acid derivative sialidase trans-sialidase Article biological activity controlled study crystal structure drug structure drug synthesis enzyme inhibition hydrogen bond ion exchange chromatography LC50 lysis molecular docking nonhuman sialylation Trypanosoma cruzi amination antagonists and inhibitors Chagas disease chemistry drug design drug effect enzymology human metabolism molecular docking parasitology structure activity relation Trypanosoma cruzi Amination Chagas Disease Drug Design Glycoproteins Humans Molecular Docking Simulation Neuraminidase Propionates Structure-Activity Relationship Trypanocidal Agents Trypanosoma cruzi 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. © 2018 Elsevier Masson SAS JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_02235234_v156_n_p252_Kashif |