Zuzana Hricovíniová

Epimerization reactions catalyzed by transition metals have changed the previous methods used in the synthesis of rare carbohydrates. In July 2024, we commemorated the 95th anniversary of the birth of Prof. Vojtech Bílik, the discoverer of a new reaction in the synthesis of rare carbohydrates. Over fifty years ago, many sugars were generally prepared by the Lobry de Bruyn–Alberda van Ekenstein isomerization reaction, which was the simplest method for a long period. However, this approach was not very efficient and the epimeric aldose was usually obtained in lower yield than the ketose. A new methodology introduced by Bílik in the 1970′s showed that the synthesis of epimeric aldoses mediated by the molybdenum Mo(VI) catalyst could significantly improve the preparation of rare aldoses without undesirable side reactions. Due to the simplicity and high efficiency of the reaction, the stereospecific Mo(VI)-catalyzed transformation of aldoses was used for preparative purposes and soon gained international recognition. The Mo(VI)-catalyzed epimerization reaction of aldoses was named after its discoverer, and it is the only reaction in the chemical literature of carbohydrates named after a Slovak scientist. On this anniversary, we take the opportunity to summarize the scientific achievements in this field of research.

Two copper(II) complexes (Cu-L1, Cu-L2) derived from 2,3-substituted quinazolinone Schiff base ligands (L1, L2) were prepared to examine their anticancer activity. Compounds were characterized using various spectroscopic methods (FTIR, NMR, UV-vis) and quantum-chemical calculations. The biological effects of Cu(II) complexes bearing quinazolinone scaffolds were evaluated on two cancers’ cell lines (breast—MCF-7 and lung—A549), as well as on untransformed cells (keratinocytes—HaCaT). Copper complexes were highly cytotoxic, with IC₅₀ in the low micromolar range, while the quinazoline ligands L1 and L2 remained inactive in inhibiting cell proliferation. Antioxidant activity was investigated in the model systems using DPPH and FRAP assays. The Cu-L1 and Cu-L2 complexes exhibited enhanced DPPH free radical scavenging efficiency compared to the L1 and L2 ligands, but their reducing ability was comparable to that of the free ligands. Evaluation of oxidative stress in vitro carried out by staining cells with various ROS-specific indicators showed reduced production of superoxide anion radical and hydrogen peroxide after treatment of cells with copper complexes. Such a negative impact on ROS formation in cells can lead to cellular redox imbalance and consequent cell death, among others, by inducing apoptosis and/or necrosis, depending on the copper complex used. We hypothesize that the high cytotoxic activity of the investigated copper complexes is apparently the result of multiple mechanisms of action, and the imbalance in the cellular antioxidant system partly contributes to the overall cytotoxic effect.

Nature has been a source of inspiration for the development of new pharmaceutically active agents. A series of new unnatural gallotannins (GTs), derived from d-lyxose, d-ribose, l-rhamnose, d-mannose, and d-fructose have been designed and synthesized in order to study the protective and antimicrobial effects of synthetic polyphenols that are structurally related to plant-derived products. The structures of the new compounds were confirmed by various spectroscopic methods. Apart from spectral analysis, the antioxidant activity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging and iron reducing power (FRAP) assays. Antibacterial activity of compounds was tested in vitro against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 (reference and control strains), three methicillin-resistant isolates of S. aureus, and three isolates of vancomycin-resistant E. faecalis. For screening of antimycobacterial effect, a virulent isolate of Mycobacterium tuberculosis and two non-tuberculous mycobacteria were used. Furthermore, antibiofilm activity of structurally different GTs against S. aureus, and their ability to inhibit sortase A, were inspected. Experimental data revealed that the studied GTs are excellent antioxidants and radical-scavenging agents. The compounds exhibited only a moderate antibacterial effect against Gram-positive pathogens S. aureus and E. faecalis and were practically inactive against mycobacteria. However, they were efficient inhibitors and disruptors of S. aureus biofilms in sub-MIC concentrations, and interacted with the quorum-sensing system in Chromobacteriumviolaceum. Overall, these findings suggest that synthetic GTs could be considered as promising candidates for pharmacological, biomedical, consumer products, and for food industry applications.

According to the last WHO report, the level of bacterial resistance is alarming all over the world. Drug resistant diseases cause at least 700 000 deaths a year [1]. The synthesis of new antibacterial compounds is an important step to overcome this problem. Shiff bases are a privileged structure possessing a wide spectrum of pharmacological activities such as anticancer, antioxidant and antibacterial [2]. The synthesis of 3‑[(2‑hydroxy‑5‑nitrobenzylidene)amino]‑2‑(2‑hydroxy‑5‑nitrophenyl)‑2,3‑dihydroquinazolin‑4(1H)‑one was described, and its spectral analysis, antioxidant and cytotoxic activities were presented [3]. The aim of this work was to study the antibacterial activity of this compound and its Cu(II) complex [4] against a spectrum of bacterial strains as well as the eradication activity against S. aureus biofilm. The compounds showed moderate antibacterial activity, which was slightly higher in the case of Cu(II) complex. The dynamics of activity against S. aureus was analyzed using the time-kill curve method, and the activity was considered as bacteriostatic. Minimum biofilm eradication activity (MBEC90) against staphylococcal biofilm was only twofold higher than MIC against planktonic cells, which shows a great potential of these derivatives as anti-biofilm active drugs. This study was supported by the Ministry of Education of the Czech Republic (LO1305) and by project VEGA 2/0022/18. References: No time to wait–securing the future from drug-resistant infections. Report to the Secretary General of the Nations, 2019, https://www.who.int/docs/default-source/documents/no-time-to-wait-securing-the-future-from-drug-resistant-infections-en.pdf?sfvrsn=5b424d7_6. Sztanke, K.; Maziarka, A.; Osinka, A.; Sztanke, M. An insight into synthetic Schiff bases revealing antiproliferative activities in vitro. Med. Chem. 2013, 21(13):2648–3666. Hricoviniova, Z. Hricovini, M.; Kozics, K. New series of quinazolinone derived Schiff’s bases: synthesis, spectroscopic properties and evaluation of their antioxidant and cytotoxic activity. Pap. 2018, 72(4): 1041–1053. Hricoviniova, Z. et al. manuscript in preparation