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 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.
Highlights
Type 2 diabetes mellitus (T2DM) is a long-lasting and progressive metabolic disease characterized by insulin resistance in several peripheral tissues such as liver, muscle, and adipose, as well as impaired insulin secretion by the pancreas [1]
Phenformin (Figure 1), activates AMPK, but in 1978 it was retired from the market due to its toxicity, producing lactic acidosis as a major side effect that prompted the withdrawal of phenformin as a treatment for diabetes [5]
Benzyl or 4-substituted phenyl groups were designed as lower homologues, with one or two methylene groups less than those presented by phenformin
Summary
Type 2 diabetes mellitus (T2DM) is a long-lasting and progressive metabolic disease characterized by insulin resistance in several peripheral tissues such as liver, muscle, and adipose, as well as impaired insulin secretion by the pancreas [1]. Metformin (a biguanide, Figure 1) is the most extensively prescribed oral antidiabetic drug for the treatment of T2DM [2]. Number of metabolic diseases such as type 2 diabetes mellitus (T2DM) [2]. Another biguanide, phenformin (Figure 1), activates AMPK, but in 1978 it was retired from the market due to its toxicity, producing lactic acidosis as a major side effect that prompted the withdrawal of phenformin as a treatment for diabetes [5]. We describe the molecular docking of the most active compounds in the nucleotide binding site on γ-subunit of AMPK, and their in vivo antihyperglycemic effect using a streptozotocin–nicotinamide rat model of noninsulin dependent diabetes mellitus
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