Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action
This work describes the design, synthesis in one step, and the in vitro, in vivo, and in silico antidiabetic evaluation of a series of ten alicyclic and aromatic (alkyl +aryl: alkaryl)biguanides, analogues of metformin and phenformin. The design was conceived using isosteric replacement, chain-ring...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2017-01-01
|
| Series: | Journal of Chemistry |
| Online Access: | http://dx.doi.org/10.1155/2017/1212609 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832567004231368704 |
|---|---|
| author | Erika Gutierrez-Lara Carlos Martínez-Conde Edgar Rosales-Ortega Juan José Ramírez-Espinosa Julio C. Rivera-Leyva David Centurión Karla Carvajal Daniel Ortega-Cuellar Samuel Estrada-Soto Gabriel Navarrete-Vázquez |
| author_facet | Erika Gutierrez-Lara Carlos Martínez-Conde Edgar Rosales-Ortega Juan José Ramírez-Espinosa Julio C. Rivera-Leyva David Centurión Karla Carvajal Daniel Ortega-Cuellar Samuel Estrada-Soto Gabriel Navarrete-Vázquez |
| author_sort | Erika Gutierrez-Lara |
| collection | DOAJ |
| description | This work describes the design, synthesis in one step, and the in vitro, in vivo, and in silico antidiabetic evaluation of a series of ten alicyclic and aromatic (alkyl +aryl: alkaryl)biguanides, analogues of metformin and phenformin. The design was conceived using isosteric replacement, chain-ring transformation, and lower and higher homologation strategies. All compounds were obtained as crystals and their structure was confirmed on the basis of their spectral data (NMR and mass spectra), and their purity was ascertained by microanalysis. Compounds were in vitro evaluated as activators of AMP-Activated Protein Kinase (AMPK). The results indicated that compounds 4, 5, and 6 showed similar or even better effect compared to metformin. Docking analysis was performed with regulatory subunit γ of AMPK, showing several interactions with nucleotide binding pocket. The in vivo evaluation of compounds 4–6 at a single dose of 50 mg/kg was performed in a murine experimental model of diabetes. The results showed an important and robust decrease of plasmatic glucose levels (−40%). Compound 6 was selected for an oral glucose tolerance test, showing an antihyperglycemic effect similar to metformin. The in vivo results indicated that compounds 4–6 may be effective in treating experimental T2DM. |
| format | Article |
| id | doaj-art-0ec2ce9d730c4f838692216134f9a468 |
| institution | Kabale University |
| issn | 2090-9063 2090-9071 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Chemistry |
| spelling | doaj-art-0ec2ce9d730c4f838692216134f9a4682025-02-03T01:02:34ZengWileyJournal of Chemistry2090-90632090-90712017-01-01201710.1155/2017/12126091212609Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic ActionErika Gutierrez-Lara0Carlos Martínez-Conde1Edgar Rosales-Ortega2Juan José Ramírez-Espinosa3Julio C. Rivera-Leyva4David Centurión5Karla Carvajal6Daniel Ortega-Cuellar7Samuel Estrada-Soto8Gabriel Navarrete-Vázquez9Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, MexicoDepartamento de Farmacobiología, Cinvestav-Coapa, 14330 Ciudad de México, MexicoLaboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, 04150 Ciudad de México, MexicoLaboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, 04150 Ciudad de México, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, MexicoThis work describes the design, synthesis in one step, and the in vitro, in vivo, and in silico antidiabetic evaluation of a series of ten alicyclic and aromatic (alkyl +aryl: alkaryl)biguanides, analogues of metformin and phenformin. The design was conceived using isosteric replacement, chain-ring transformation, and lower and higher homologation strategies. All compounds were obtained as crystals and their structure was confirmed on the basis of their spectral data (NMR and mass spectra), and their purity was ascertained by microanalysis. Compounds were in vitro evaluated as activators of AMP-Activated Protein Kinase (AMPK). The results indicated that compounds 4, 5, and 6 showed similar or even better effect compared to metformin. Docking analysis was performed with regulatory subunit γ of AMPK, showing several interactions with nucleotide binding pocket. The in vivo evaluation of compounds 4–6 at a single dose of 50 mg/kg was performed in a murine experimental model of diabetes. The results showed an important and robust decrease of plasmatic glucose levels (−40%). Compound 6 was selected for an oral glucose tolerance test, showing an antihyperglycemic effect similar to metformin. The in vivo results indicated that compounds 4–6 may be effective in treating experimental T2DM.http://dx.doi.org/10.1155/2017/1212609 |
| spellingShingle | Erika Gutierrez-Lara Carlos Martínez-Conde Edgar Rosales-Ortega Juan José Ramírez-Espinosa Julio C. Rivera-Leyva David Centurión Karla Carvajal Daniel Ortega-Cuellar Samuel Estrada-Soto Gabriel Navarrete-Vázquez Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action Journal of Chemistry |
| title | Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action |
| title_full | Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action |
| title_fullStr | Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action |
| title_full_unstemmed | Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action |
| title_short | Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action |
| title_sort | synthesis and in vitro ampk activation of cycloalkyl alkarylbiguanides with robust in vivo antihyperglycemic action |
| url | http://dx.doi.org/10.1155/2017/1212609 |
| work_keys_str_mv | AT erikagutierrezlara synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT carlosmartinezconde synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT edgarrosalesortega synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT juanjoseramirezespinosa synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT juliocriveraleyva synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT davidcenturion synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT karlacarvajal synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT danielortegacuellar synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT samuelestradasoto synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction AT gabrielnavarretevazquez synthesisandinvitroampkactivationofcycloalkylalkarylbiguanideswithrobustinvivoantihyperglycemicaction |