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The direct synthesis of thiazolidine derivatives with polypharmacological properties as potential drugs

Work number - M 19 FILED

The aim of this work was the design of novel "drug-like" molecules based on thiazolidine as potential antiparasitic and/or antitumor agents. The original regio- and stereoselective methods of synthesis of heterocyclic compounds based on the reactions of [2+3]-, [2+4]- and [3+3]-cycloadditions have been elaborated. A series of new hybrid molecules containing pharmacologically attractive fragments of thiazole, 4-thiazolidinone, thiopyranothiazole, thiazolopyridine, indole, imidazothiadiazole, etc. have been obtained. A structure modification of polycondensed thiopyranothiazoles at the NH-acidic centre in N3 position of the basic core was performed, which yielded a row of 3-substituted derivatives. In general, nearly 200 new heterocyclic molecules have been obtained for further pharmacological evaluation. Structure and purity of the synthesized compounds were confirmed by the methods of 1Н and 13С NMR-spectroscopy, LCMS and X-ray analysis. Screening of the anti-parasitic activity (in vitro) was conducted towards unicellular parasites of Trypanosoma and Leishmania genera. Anticancer assays were performed according to the US NCI protocol on 60 cell lines representing leukemia, melanoma, lung cancer, colon, CNS, ovarian, renal, prostate and breast cancers. The biological studies reveled the identification of 36 highly active and low-toxic compounds with anticancer and trypanocidal activities in micromolar and submicromolar concentrations, which indicates the prominence for their further in-depth study as potential drugs. Based on the results of the biological activity of synthesized compounds, the structure-activity relationship and the correlation of the antitumor and antiparasitic effects have been performed, as well as the approaches for the rational design of potential anticancer and antitrypanosomal agents have been developed.

According to the results of presented work a number of scientific articles have been published; about 80% of which were published in the international peer-reviewed journals with impact factors (0.7-4.8). A patent application for the invention "Novel derivatives of 2-hydrazono-4-thiazolidinone and 2-hydrazonothiazole exhibiting anti-trypanosomal activity" No. a201902077 from 03/01/2019 had been applied.

Number of publications: 25, incl. 2 monographs, 23 articles (13 - in peer-reviewed journals with impact factor). The total number of citations of the authors' publications is 431/h-index, according to the databases: Web of Science - 200/8, Scopus - 315/10, Google Scholar - 431/11. 1 Patent of Ukraine had been received.