Novel sulfonyl(thio)urea derivatives act efficiently both as insulin secretagogues and as insulinomimetic compounds

• Sulfonylthiourea 7 triggers GLUT4 expression and translocation on skeletal muscle.
• This compound acts as both insulin secretagogue and as insulinomimetic.
• Mechanism of sulfonylthiourea 7 on glycemia involves PI-3K and PKA activity.

Glibenclamide is widely used in the management of non-insulin dependent diabetes mellitus, but numerous risks limit its use in therapy. In the search for novel structures that are safer and more efficient than glibenclamide, we obtained new chemical analogs based on bioisosterism, through the treatment of benzenesulfonamide derivatives with isothiocyanates and isocyanates, affording (thio)ureas with good yield. We also verified the hypoglycemic activity, through an in vivo approach. Most of these synthesized compounds improved glucose tolerance, and the mechanism of action of the best compound (7) suggests that its effect is mediated by insulin secretion, while its hypoglycemic action is triggered by glucose uptake involving GLUT4 expression and translocation through PI-3K and PKA activity and active de novo protein synthesis in skeletal muscle. Taking all these factors together, sulfonylthiourea 7 acts as an insulin secretagogue and insulinomimetic agent on glucose homeostasis, and does not exhibit toxicity in acute treatment.

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