Targeted search of hypoglycemic agents among N-substituted isoindoline-1,3-diones and its analogues

Abstract

It is known, that increasing of glucose level in the blood is an important factor at the risk of vascular complications in diabetes mellitus type 2 development. Taking this into account, short-acting priming regulators of glycemia (meglitinides) are designed, such as tableted sugar-reducing drugs with short acting insulin secretion stimulation. They are characterized by a slight decrease of glycohemoglobin content, the risk of body weight gain and decrease of efficacy during long-term usage despite their effectiveness. The solution of this problem can be as following: the creation of more effective drugs, which would contain known antidiabetic “pharmacophore” fragments able to provide a long-term hypoglycemic effect and having a polyvectoral mechanism of activity and effect both on symptoms of the disease and on disease etiology. The aim of the work is targeted search of hypoglycemic isoindoline-1,3-dione derivatives and its hydrogenated analogues based on rational design, structural similarity to metglitinides, molecular docking and traditional pharmacological screening. Materials and methods: laboratory utensils and organic solvents, “Stuart Scientific SMP30” melting point apparatus, ELEMENTAR vario EL Cube elemental analyzer, Bruker ALPHA FT-IR spectrometer, Varian-Mercury 400 1H NMR spectrometer, Agilent 1100 Series liquid chromatograph, Marvin Sketch 17.21, AutoDockTools-1.5.6, Discovery Studio 4.0. Results. The targeted search of hypoglycemic agents among N-substituted isoindoline-1,3-diones and its analogues based on the structural similarity with existing active pharmaceutical ingredients, using molecular docking and traditional pharmacological screening was performed in the work. Mentioned compounds were synthesized by the refluxing of phthalic anhydride and its analogs with aminoalkyl-(alkaryl-,aryl-)carboxylic acids in the medium of the acetic acid. It was shown, that refluxing of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione with glycine under the given conditions resulted the retro Diels-Alder reaction and formation of (Z)-4-((carboxymethyl)amino)-4-oxobut-2-enoic acid. Elemental analysis, chromatomass-, IR- and 1H-NMR spectral methods were used to prove the structure and individuality of the synthesized compounds. Conclusion. A number of compounds were synthesized and chemically modified. Research of their hypoglycemic activity was carried out, that raveled a number of high active substances. Certain “structure – activity relations” were established and the perspective directions of their further chemical modification were substantiated.

Keywords

• carboxylic acids
• molecular docking simulation
• synthesis
• magnetic resonance spectroscopy
• hypoglycemic agents