Four 4-hydroxycoumarin derivatives were synthesized and the structure was confirmed by NMR spectroscopy and Mass spectrometry. Tested compounds have shown significant antimicrobial activity against Bacillus subtilis subsp. spizizenii, Bacillus cereus, Staphylococcus aureus, and Staphylococcus epidermidis, and the effect of more halogens on the benzene nucleus, as well as the combination of halogen and alkyl groups, on the antimicrobial activity, was investigated. According to the docking study, these compounds can operate simultaneously on two enzymes, amylase and gyrase (1BAG and 1KZN), which are known to play an important role in bacterial life. Obtained docking study parameters for tested compounds showed an association with the in vitro results of the antimicrobial activity of these compounds. In silico tests of molecular properties of the tested compounds showed that the compounds met Lipinski's rule of five. In this paper, the ADME parameters of tested compounds were also calculated: Caco2 (in vitro Caco2 cell permeability), HIA (human intestinal absorption), MDCK (in vitro Mandin Darby Canine Kidney (MDCK) cell permeability), TPSA (topological polar surface area), etc.

Abstract Twelve previously synthesized, biologically active 2,6,7-trihydroxyxanthen-3-one derivatives were evaluated in vitro for antiproliferative activity. Compounds were screened against HeLa, SW620, HepG2 and A549 tumor cell lines. Compound with the trifluormethyl group on C-4’ position of the phenyl ring showed the best inhibitory activity towards HeLa and A549 tumor cells with IC50 of 0.7 and 4.1 µmol L−1, resp. Compound with chlorine and fluorine substituents on aryl ring showed the best antiproliferative activity against SW620 with IC50 of 4.1 µmol L–1 and against HepG2 tumor cell line with IC50 of 4.2 µmol L–1. Analyses of cytotoxic and genotoxic potential of the trifluormethyl derivative were performed with cytokinesis-block micronucleus cytome assay in human lymphocyte culture and revealed no genotoxic and cytotoxic effects. The most potent compounds were subjected to molecular docking simulations in order to analyse bindings to molecular targets and, at the same time, further support the results of experimental cytotoxic tests. Docking studies showed sites of importance in forming hydrogen bonds of the most potent compounds with targets of interest.

Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (1H, 13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R β) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.

Ten biologically active 2,2,5,5-tetramethyl-9-aryl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives were synthesized and their structures were confirmed by IR, 1H and 13C NMR spectroscopy and mass spectrometry. Synthesized compounds were scanned for their antioxidant, antimicrobial and antiproliferative activity. Antibacterial activity was tested by the diffusion and dilution method against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, while antifungal activity was tested against Candida albicans and Saccharomyces cerevisiae. Antiproliferative activity was tested against HeLa (cervical carcinoma), SW620 (colorectal adenocarcinoma, metastatic), hepatocellular carcinoma (HEpG2), lung carcinoma cells (A549) and mouse embryo fibroblast cell line (3T3). The best antioxidant activity showed compound 2 with two hydroxy groups substituted on phenyl ring in positions 2' and 3'. The best antimicrobial activity of all synthesized compounds showed compound 8, while the best antiproliferative activity showed compound 6. Results signify the importance of xanthene-1,8-dione derivatives as potential antioxidant and antiproliferative agents.

Oxidative stress is directly related to several diseases and symptoms, where antioxidant compounds, such as xanthenes, may become important in prevention and/or treatmant. Ten biologically active 9-aryl substituted 2, 6, 7-trihydroxyxanthen-3-one derivatives were synthesized using reliable one-pot synthesis and their structures were confirmed by IR, 1H and 13C NMR spectroscopy and mass spectrometry. Some of the synthesized compounds were scanned for their antioxidant potency using electrochemical method cyclic voltammetry of immobilized microparticles. Substitution of hydrogen at the phenyl ring of 2, 6, 7-trihydroxy-9-phenylxanthen-3-one with an electron-donating group affected the reducing power of the compounds by lowering the biological oxidation potential. These results signify the importance of xanthen-3-one derivatives as antioxidant agents and their further biological evaluation.

For some synthesized coumarin derivatives, 1H and 13C NMR isotropic chemical shifts and some other molecular properties were calculated using density functional theory. The calculations yield reliable results, that are in good correlation with experimental data. This is a good basis for the collaboration between experimentalists and quantum chemists.

The efficient syntheses of 5-(2-hydroxyethyl)- and 5-(3-hydroxypropyl)-substituted pyrimidine derivatives bearing 2,3-dihydroxypropyl, acyclovir-, ganciclovir- and penciclovir-like side chains are reported. A synthetic approach that included the alkylation of an N-anionic-5-substituted pyrimidine intermediate (method A) provided the target acyclonucleosides in significantly higher overall yields in comparison to those obtained by method B using sylilation reaction. The phosphorylation assays of novel compounds as potential substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK) showed that solely pyrimidine 5-substituted acyclonucleosides with a penciclovir-like side chain acted as a fraudulent substrates of HSV-1 TK. Moreover, the uracil derivative with penciclovir-like side chain with less bulky 2-hydroxyethyl substituent at C-5 proved to be a better substrate than the corresponding one with a 3-hydroxypropyl substituent. Therefore, this acyclonucleoside was selected as a lead compound for the development of a positron emission tomography HSV-1 TK activity imaging agent.