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Journal of Chemistry
Volume 2017, Article ID 1212609, 8 pages
https://doi.org/10.1155/2017/1212609
Research Article

Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action

1Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, MOR, Mexico
2Departamento de Farmacobiología, Cinvestav-Coapa, 14330 Ciudad de México, Mexico
3Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, 04150 Ciudad de México, Mexico

Correspondence should be addressed to Samuel Estrada-Soto; xm.meau@hcone and Gabriel Navarrete-Vázquez; xm.meau@eterravan_leirbag

Received 16 August 2017; Accepted 22 October 2017; Published 15 November 2017

Academic Editor: Teodorico C. Ramalho

Copyright © 2017 Erika Gutierrez-Lara et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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 46 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 46 may be effective in treating experimental T2DM.