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Synthesis and in vivo Evaluation of Fluorobenzyl Metformin Derivatives as Potential Drugs in The Diabetes Treatment

Von Wiley-VCH zur Verfügung gestellt

Can metformin be improved? herein we synthesize a family of non-described fluorobenzyl metformin derivatives to enhance its activity and biocompatibility. Once obtained, those have been characterized and an enzymatic assay carried out to pick the best prospects for a in vivo assay, answering the current question, having obtained improved, biocompatibility speaking, metformin derivatives.


Metformin is a versatile, biocompatible, and cheap bis-guanidine used as first response line in the type II diabetes treatment. Since its first human trials (1956) several structural modifications were carried out to increase its activity. However, with this augmented activity, the biological compatibility diminishes, generating serious side effects, such as lactic acidosis. Considering that cytochrome P450 oversees the metformin metabolism and its weakness to eliminate fluorinated metabolites; we envisioned the synthesis of benzyl fluorinated metformin derivatives. In our hypothesis the fluorine atoms can give, by inductive effect, a higher acidity to the hydrogen in the benzylic nitrogen, increasing its solubility. On the other hand, fluorine would give resistance to cP450 allowing the molecule acting longer. Thus, a family of fourteen fluorobenzyl metformins were synthesized and characterized, then an in vitro enzymatic assay with α-amylase was performed to select the five best performing compounds, then an in vivo experiment was carried out with streptozotocin-induced CD1 mice using the selected derivatives. Blood glucose was measured every day. After sacrifice, the lipid profile, serum, and liver γ-glutamyl transferase (GGT) activity determined the biocompatibility. Results showed two compounds (1 L and 1 M) with enhanced activity and higher biocompatibility for blood glucose, lipids metabolism and GGT activity regulation.

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