Development of new 3-aminopyridone derivatives with potential geroprotective activity
2025-07-23 11:29
Development of new 3-aminopyridone derivatives with potential geroprotective activity
Project goal:Based on biologically active derivatives of 3-aminopyridone, synthesize leader molecules with potential geroprotective activity, confirmed experimentally in vitro and in vivo.
Project description: The “geroprotective activity” refers to the combination of effects exerted by the test substances under in vitro (senolytic effect, stimulation of autophagy in cultures with a cellular senescence phenotype) and in vivo (correction of the manifestations of the metabolic syndrome in rats – an example of age-associated pathology) conditions. The problem of the lack of clinically proven geroprotective drugs is partly determined by the too small base of available biologically active substances that exhibit senolytic activity in vitro and stimulate autophagy in cell aging models and are capable of preventing or inhibiting the development of age-associated pathology in vivo. Aminopyridones are a class of heterocycles with a relatively high potential for biological activity. Among them, 3-aminopyridones stand out, for which antioxidant and cytoprotective effects have been recorded (these effects can be considered as forerunners of senolytic action). It is assumed that the cytoprotective properties, the ability to inhibit the development of oxidative stress and hyperglycemia in cell cultures, previously identified in 3-aminopyridone derivatives, may predetermine the geroprotective potential, and screening of new derivatives will make it possible to identify the leader compounds according to these characteristics.
The hypothesis of the project: on the basis of 4-methyl-(aryl-, hetaryl) substituted 3-aminopyridones, the synthesis of new derivatives with pronounced geroprotective properties is probable. The project is aimed at solving the problem of the lack of substances with geroprotective activity that are promising for clinical trials.
Project facilitators: PI: Alexander Gulyaev Zarina Shulgau Shynggys Sergazy Assel Urazbayeva Ivan Kulakov
Realisation period: 2023-2025
Expected results: The development of methods for introducing new pharmacophore groups into the structure of 3-aminopyridone will hypothetically make it possible to enhance biological activity and synthesize original, new objects with geroprotective potential. Under the conditions of in vitro experiments on cell cultures with accelerated aging and in vivo on the model of metabolic syndrome in rats, it is expected to identify leader compounds with a proven potential for geroprotective activity.
Based on the results of the research, publications will be published in peer-reviewed scientific journals indexed in the Science Citation Index Expanded Web of Science database and (or) having the corresponding CiteScore percentile in the Scopus database in the amount corresponding to one of the requirements of paragraph 7 of subparagraph 1 of the Competitive documentation for grant funding of scientific and (or) scientific and technical projects for 2023-2025, for industries in the field of medicine and healthcare, for applied research.
Methodology: I. Together with partners from the Institute of Chemistry of the Tyumen State University (Tyumen State University, Russia), develop possible methods for introducing new pharmacophore groups into the structure of 3-aminopyridone in order to enhance the potential biological activity and their bioavailability. Synthesize new derivatives of 4-methyl- (aryl-, hetaryl) substituted 3-aminopyridones. Prepare and register the spectral characteristics of the synthesized new compounds in order to fully prove their structure. Conduct a computer forecast using the computer module PASS and QSAR. At least 20 new substances.
II. In vitro screening of new 3-aminopyridones for the ability to exhibit antioxidant, cytoprotective, senolytic activity and the ability to stimulate autophagy in cell cultures with an accelerated aging phenotype. Selection of the most promising compounds for in vivo studies.
III. Determination of the possibility of selected substances to correct the manifestations of the metabolic syndrome in rats (obesity, hypertension, diabetes mellitus, osteoporosis, steatohepatosis). Isolation of substances with activity exceeding the activity of standard preparations.
IV. Analysis of the results, identification of leader compounds with proven potential for geroprotective activity for possible patenting and further in-depth preclinical studies and clinical trials.