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

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 , , and showed similar or even better effect compared to metformin. Docking analysis was performed with regulatory subunit of AMPK, showing several interactions with nucleotide binding pocket. The in vivo evaluation of compounds -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 was selected for an oral glucose tolerance test, showing an antihyperglycemic effect similar to metformin. The in vivo results indicated that compounds -may be effective in treating experimental T2DM.

Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

“…The samples of blood were collected from the caudal vein at 0, 1, 3, 5 and 7 h after administration of each compound. Blood glucose levels were estimated using a commercial glucometer [ 41 , 42 , 43 ]. The percentage variation of glycemia for each group was calculated.…”

Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect

“…The following pharmacokinetic properties were acquired using AdmetSAR and SwissADME software: consensus logP, water solubility class, human intestinal absorption, blood-brain permeability, P-glycoprotein substrate, bioavailability score, and inhibition of CYP3A4. Toxicological profiles (Ames, hERG channel blockage, and carcinogenesis) were obtained from the web server AdmetSAR and ACD/Tox Suite version 2.95 [22,23,44]. To visualize the pharmacological consensus analysis, we used a color code indicating chances that the compound has drug-like properties, as follows: green (very satisfactory), yellow (satisfactory), and red (unsatisfactory).…”

Triterpenos de Hibiscus sabdariffa L. con efecto multimodal PPARδ/γ y AMPKα1: estudios in vivo, in vitro e in silico

“…El AMP se une en la subunidad γ de AMPK, lo cual da origen a un cambio conformacional que favorece la exposición de un sitio de fosforilación importante para la activación de esta cinasa. Aunado a dicho evento de acoplamiento, debe ocurrir un evento de fosforilación en la subunidad α en Thr172, determinante para que ocurra la activación completa de AMPKα1 [124]. Además se ha reportado que la activación de esta cinasa promueve la translocación de GLUT4 a la membrana plasmática [125].…”

“…Los resultados de la presente investigación van dirigidos al estudio de la acción agonista dual para PPARδ/γ y activación de AMPKα1, de los compuestos aislados de H. sabdariffa. Algunos de los fármacos más utilizados para el tratamiento de la DT2 es la metformina, con efectos sobre la activación de AMPKα1 [124].…”