Development of medicines based on 5-phenyltetrazole derivatives for the pharmacological correction of metabolic phenomena

Introduction. Many compounds containing a tetrazole component are superior in efficacy to other antidiabetic drugs in preclinical studies, and some candidates are already in current trials. The widespread use of tetrazole derivatives to target diabetes-associated targets and therapies that maintain their stability provide the basis for the development of new, effective antidiabetic agents.

Aim. A study (in silico, synthesis, in vivo) of a series of hybrid 5-phenyltetrazole derivatives was conducted to identify and conduct experimental validation of promising compounds exhibiting hypoglycemic and anti-fat activity.

Materials and methods. The synthesis of hybrid heterocyclic compounds was accomplished by acylation of a series of heterocyclic derivatives of N-alkyl-5-aminotetrazole, 4-amino-4H-1,2,4-triazole-3-thiol, and 2-hydrazinyl-4,6-dimethylpyrimidine with 5-phenyltetrazol-2-ylacetic acid chloride.

Results and discussion. As a result of in silico (PASS, docking, scoring) study of biological activity in a series of 5-phenyltetrazole derivatives, the most promising "hybrid" (polynuclear) heterocyclic compounds were identified: N'-(4,6-dimethylpyrimidin-2-yl)-2-(5-phenyl-2H-tetrazol-2-yl)-acetohydrazide, N-(3-mercapto-4H-1,2,4-triazol-4-yl)-2-(5-phenyl-2H-tetrazol-2-yl)-acetamide, N-(1-methyl-1H-tetrazol-5-yl)-2-(5-phenyl-2H-tetrazol-2-yl)-acetamide, N-(2-methyl-2H-tetrazol-5-yl)-2-(5-phenyl-2H-tetrazol-2-yl)-acetamide and N-tert-butyl-2-({1-[2-(5-phenyl-2H-tetrazol-2-yl)acetamido]-1H-tetrazol-5-yl}thio)acetamide. These predictions are of interest as potential computer-aided means for the pharmacological correction of various metabolic phenomena. A rational method for synthesizing these compounds was developed and implemented, the structure and individuality of which were demonstrated using modern instrumental physicochemical methods. In vivo studies demonstrated that these heterocyclic compounds exhibit hypoglycemic and pronounced anti-lipid activity.

Conclusion. The study of hybrid 5-phenyltetrazole derivatives revealed pronounced hypoglycemic activity. It was found that the anti-lipid activity in this case is not directly related to the hypoglycemic effect, unlike the manifestation characteristic of the sensitizer metformin.

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