Potent ribonucleotide reductase inhibitors: Thiazole-containing thiosemicarbazone derivatives.

The antioxidant, antimalarial, antibacterial, and antitumor activities of thiosemicarbazones have made this class of compounds important for medicinal chemists. In addition, thiosemicarbazones are among the most potent and well-known ribonucleotide reductase inhibitors. In this study, 24 new thiosemicarbazone derivatives were synthesized, and the structures and purity of the compounds were determined by IR, 1 H NMR, 13 C NMR, mass spectroscopy, and elemental analysis. The IC50 values of these 24 compounds were determined with an assay for ribonucleotide reductase inhibition. Compounds 19, 20, and 24 inhibited ribonucleotide reductase enzyme activity at a higher level than metisazone as standard. The cytotoxic effects of these compounds were measured on the MCF7 (human breast adenocarcinoma) and HEK293 (human embryonic kidney) cell lines. Similarly, compounds 19, 20, and 24 had a selective effect on the MCF7 and HEK293 cell lines, killing more cancer cells than cisplatin as standard. The compounds (especially 19, 20, and 24 as the most active ones) were then subjected to docking experiments to identify the probable interactions between the ligands and the enzyme active site. The complex formation was shown qualitatively. The ADME (absorption, distribution, metabolism, and excretion) properties of the compounds were analyzed using in-silico techniques.

Electroreduction of aromatic oximes: diprotonation, adsorption, imine formation, and substituent effects.

Aromatic oximes are reduced in aqueous solution in a four-electron process. The reducible species in the pH range 5-8 is a diprotonated form of the oxime. This species is generated in the course of electrolysis in the vicinity of the electrode surface from the adsorbed neutral form of the oxime. The reduction is initiated by a cleavage of the N-O bond. The diprotonation facilitates the reduction process by the preformation of OH2+ as a good leaving group and by a positive charge on the azomethine nitrogen. Diprotonation has been proven based on shapes of i = f(pH) plots, by observed shifts of half-wave potentials with pH and by comparison with the reduction of nitrones. Some observed deviations from theoretical i = f(pH) plots were attributed to the role of adsorption on the rate of protonation. Adsorption is also responsible for dips on some of the i-E curves. Adsorption plays a role at concentrations as low as 1 x 10(-5) M, when the electrode surface is still not fully covered. This indicates that catalyzed protonation occurs on islets of adsorbed materials. At pH 2-5 the studied oximes in the vicinity of the electrode are predominately present in a protonated form, which is less strongly adsorbed. In this pH range the protonation takes place in a homogeneous reaction layer of the electrode. It yields a monoprotonated form, which is reduced. The separation of two two-electron waves observed for some oximes in acidic media serves as an experimental proof of the formation of imines as reduction intermediates. This separation is caused by the differences in pKa values of protonated forms of oximes and imines. The effects of substituents in the para position on the benzene ring are characterized by correlation with the Hammett substituent constant sigmax. This has been proven at pH 1.5 for substituted benzaldehyde oximes and at pH 5.0 for substituted acetophenone oximes.