A series of isatin Schiff base derivatives were identified during in silico screening of the small molecule library for novel activators of p53. The compounds selected based on molecular docking results were further validated by a high-content screening assay using U2OS human osteosarcoma cells with an integrated EGFP-expressing p53-dependent reporter. The hit compounds activated and stabilized p53, as shown by Western blotting, at higher rates than the well-known positive control Nutlin-3. Thus, the p53-activating compounds identified by this approach represent useful molecular probes for various cancer studies.KEYWORDS: in silico, isatin Mannich and Schiff bases, p53 activators, in vivo assay, protein−protein interactions, MDM2

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It has been shown earlier that the interaction of Ntert-butyl-1-aza-1,3-enes with substituted benzimidazole-2-thiols leads to the formation of polynuclear sulfur-containing heterocyclic compounds, viz., benzo [4,5]As a continuation of this research in the present work data are reported on the reaction of structural analogs of benzimidazole-2-thiols, viz., substituted imidazole-2-thiones, with phenylpropiolic aldehyde tert-butylimine (Scheme 1).The reaction proceeds under stirring at 60°C for 2 h. Target compounds IVa-IVc were isolated with yields of 50-70% as crystal compounds melting with the decomposition. Their structure was confirmed by the data of 1 H and 13 C NMR spectroscopy. Thus, in the 1 H NMR spectrum (IVa) the doublet at 6.26 ppm (J = 4.9 Hz) corresponds to the proton H 1 . The signal H 2 of the thiazine ring appears as a doublet at 6.66 ppm (J = 8.8 Hz). A doublet of doublets at 6.16 ppm (J = 8.8, 4.9 Hz) corresponds to the proton H 3 of the hydroxy group. Protons of two methyl groups and protons of aromatic rings appear in the typical regions.As in case of substituted benzimidazole-2-thiols [1, 2] the initially formed imidazo[2,1-b][1,3]thiazine-5tert-butylamines (IIIa-IIIc) undergo hydrolysis with the formation of imidazo[2,1-b][1,3]thiazin-5-ols (IVa-IVc). The hydrolytic cleavage of tert-bytylamine from imidazo[2,1-b]-[1,3]thiazine-5-tert-bytylamines (IIIa-IIIc) is due to the presence of minor quantities of water in the solvent [3].As a result of the addition of 4-phenyl-2-imidazole-2-thione (IIc) to imine I, the formation of two

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